Bicyclic aryl-sulfonic acid [1,3,4]-thiadiazol-2-yl-amides, processes for their preparation, pharmaceutical compositions and methods for their use

ABSTRACT

The present invention comprises bicyclic aryl-sulfonic acid [1,3,4]-thiadiazol-2-yl-amides, their functional derivatives thereof as well as their physiologically acceptable salts and pharmaceutical compositions thereof that exhibit peroxisome proliferator activated receptor (PPAR) PPARdelta and PPARgamma agonist activity. The structure of the compounds of the invention are defined by Formula I below, 
                         
wherein the various substituents are defined herein, including their physiologically acceptable salts. Processes for the preparation of compounds are also disclosed. The compounds are suitable for the treatment of fatty acid metabolism and glucose utilization disorders, disorders relating to insulin resistance are involved as well as demyelinating and other neurodegenerative disorders of the central and peripheral nervous system.

This application is a Divisional of application Ser. No. 12/062,759,filed Apr. 4, 2008, which is a Continuation of International PatentApplication No. PCT/EP2006/009300, filed Sep. 26, 2006, all of which areincorporated herein by reference in their entireties.

The invention relates to Bicyclic aryl-sulfonic acid[1,3,4]thiadiazol-2-yl-amides and to their physiologically acceptablesalts and physiologically functional derivatives showing PPAR agonisticactivity.

Benzenesulfonamino compounds which bind to PPARs are described in WO2005/005421. Sulfonamide compounds showing hypoglycemic activity aredisclosed in Khimiko-Farmatsevticheskii Zhurnal (1987), 21(8), 965-8.From WO 97/40017 compounds having a phenyl group linked to heterocyclesare known as modulators of molecules with phosphotyrosine recognitionunits.

The invention is based on the object of providing compounds which permittherapeutically utilizable modulation of lipid and/or carbohydratemetabolism and are thus suitable for the prevention and/or treatment ofdiseases such as type 2 diabetes and atherosclerosis and the diversesequelae thereof. Another purpose of the invention is to treatdemyelinating and other neurodegenerative disorders of the central andperipheral nervous systems.

A series of hitherto unknown compounds which modulate the activity ofPPA receptors has been found. The compounds are suitable in particularfor activating PPARdelta or PPARdelta and PPARgamma, however it ispossible that the relative activation varies depending on the specificcompounds.

The compounds of the present invention are described by formula I:

wherein

-   R1 is (C1-C6) alkyl, (C0-C6) alkylene-(C3-C6) cycloalkyl, (C0-C6)    alkylene-O—(C1-C6) alkyl, (C0-C6) alkylene-O—(C3-C6) cycloalkyl,    (C0-C6) alkylene-(C6-C14) aryl, (C0-C6) alkylene-(C5-C15)    heteroaryl, wherein alkyl, alkylene, aryl, heteroaryl and cycloalkyl    can be unsubstituted or mono, di- or tri substituted by F, Cl, Br,    OCF₃, CN, CO—(C1-C6) alkyl, COO(C1-C6) alkyl, CON((C0-C6)    alkylene-H)((C0-C6) alkylene-H), S(O)_(m) (C1-C6) alkyl;-   R2, R3, R4, R5 are independently H, halogen, (C1-C6) alkyl, (C0-C4)    alkylene-O—(C0-C4) alkylene-H, CN, COO(C1-C6) alkyl,    CON((C0-C6)alkylene-H)((C0-C6)alkylene-H), S(O)_(m)(C1-C6) alkyl,    wherein alkyl and alkylene are unsubstituted or mono, di- or    trisubstituted by F;-   A is (C6-C14) aryl or (C4-C10) heteroaryl;-   n is 1, 2, 3;-   m, z are 0, 1, 2;-   R6, R7, R8 are independently H, (C1-C6) alkyl, CN, CO—(C1-C6) alkyl,    COO—(C1-C6) alkyl, CON((C0-C6) alkylene-H((C0-C6) alkylene-H),    S(O)_(m)(C1-C6) alkyl, N((C0-C6) alkylene-H)((C0-C6) alkylene-H),    N((C0-C6) alkylene-H)—CO—(C1-C6) alkyl, N((C0-C6)    alkylene-H)—CO—(C1-C6) alkyl, halogen, (C0-C6) alkylene-O—(C0-C6)    alkylene-H, (C0-C6) alkylene-(C6-C14) aryl, (C0-C6)    alkylene-O—(C6-C14) aryl, SCF3, S(O)2CF3, NO2, wherein alkyl, aryl    and alkylene are unsubstituted or mono, di- or trisubstituted by F    and aryl can be unsubstituted or monosubstituted by CF₃;    in all its stereoisomeric forms, enantiomeric forms and mixtures in    any ratio, and its physiologically acceptable salts and tautomeric    forms.

Another embodiment according to the invention are compounds of theformula 1, where

-   R1 is (C1-C6) alkyl, (C0-C6) alkylene-(C3-C6) cycloalkyl, (C0-C6)    alkylene-O—(C1-C6) alkyl, (C0-C6) alkylene-O—(C3-C6) cycloalkyl,    (C0-C6) alkylene-(C6-C14) aryl, wherein alkyl, alkylene, aryl, and    cycloalkyl can be unsubstituted or mono, di- or tri substituted by    F, Cl, Br;-   R2, R3, R4, R5 are independently H, halogen, (C1-C6) alkyl, (C0-C4)    alkylene-O—(C0-C4) alkylene-H, wherein alkyl and alkylene are    unsubstituted or mono, di- or trisubstituted by F;-   A is (C6-C14) aryl or (C4-C10) heteroaryl;-   n is 1, 2;-   z is 1, 2;-   R6, R7, R8 are independently H, (C1-C6) alkyl, CN, halogen, (C0-C6)    alkylene-O—(C0-C6) alkylene-H, (C0-C6) alkylene-(C6-C14) aryl,    (C0-C6) alkylene-O—(C6-C14) aryl, SCF3, S(O)2CF3, wherein alkyl,    aryl and alkylene are unsubstituted or mono, di- or trisubstituted    by F and aryl can be unsubstituted or monosubstituted by CF3;    in all its stereoisomeric forms, enantiomeric forms and mixtures in    any ratio, and its physiologically acceptable salts and tautomeric    forms.

Another embodiment according to the invention are compounds of theformula 1, where

-   R1 is (C1-C6) alkyl, (C0-C6) alkylene-(C3-C6) cycloalkyl, (C0-C6)    alkylene-(C6-C14) aryl, wherein alkyl, alkylene, aryl, and    cycloalkyl can be unsubstituted or mono, di- or tri substituted by    F;-   R2, R3, R4, R5 are independently H, halogen, (C1-C6) alkyl, (C0-C4)    alkylene-O—(C0-C4) alkylene-H, wherein alkyl and alkylene are    unsubstituted or mono, di- or trisubstituted by F;-   A is (C6-C14) aryl or (C4-C10) heteroaryl;-   n is 1, 2;-   z is 1;-   R6, R7, R8 are independently H, (C1-C6) alkyl, CN, halogen, (C0-C6)    alkylene-O—(C6-C14) aryl, (C0-C6) alkylene-O—(C0-C6) alkylene-H,    wherein alkyl and alkylene are unsubstituted or mono, di- or    trisubstituted by F and aryl can be unsubstituted or monosubstituted    by CF3;    in all its stereoisomeric forms, enantiomeric forms and mixtures in    any ratio, and its physiologically acceptable salts and tautomeric    forms.

Another embodiment according to the invention are compounds of theformula 1, where

-   R1 is (C1-C6) alkyl, (C0-C6) alkylene-(C3-C6) cycloalkyl, (C0-C6)    alkylene-(C6-C14) aryl, wherein alkyl, alkylene, aryl, and    cycloalkyl can be unsubstituted or mono, di- or tri substituted by    F;-   R2, R3, R4, R5 are independently H, halogen, (C1-C6) alkyl, (C0-C4)    alkylene-O—(C0-C4) alkylene-H, wherein alkyl and alkylene are    unsubstituted or mono, di- or trisubstituted by F;-   A is phenyl, pyridine or thiophene;-   n is 1;-   z is 1;-   R6 is in ortho position and F, Cl, Br, or O(C1-C4)-alkyl;-   R7 is in para position and F, Cl, Br, CH3 or CF3;-   R8 is H;    in all its stereoisomeric forms, enantiomeric forms and mixtures in    any ratio, and its physiologically acceptable salts and tautomeric    forms.

Another embodiment according to the invention are compounds of theformula 1, where

-   R1 is (C1-C4) alkyl, (C0-C2) alkylene (C3-C6) cycloalkyl, (C0-C2)    alkylene-(C6-C10) aryl, wherein alkyl, aryl, and cycloalkyl can be    unsubstituted or mono, di- or trisubstituted by F;-   R2 is H, halogen, (C1-C6) alkyl, O—(C0-C4) alkylene-H, wherein alkyl    and alkylene are unsubstituted or mono, di- or trisubstituted by F;-   R3 is H;-   R4 is H;-   R5 is H, (C1-C4) alkyl;-   A is (C6) aryl or (C5-C6) heteroaryl;-   n is 1, 2;-   z is 1;-   R6 is (C1-C4) alkyl, halogen, (C0-C2) alkylene-O—(C0-C6) alkylene-H,    (C0-C2) alkylene-(C6-C10) aryl, wherein alkyl, aryl and alkylene are    unsubstituted or mono, di- or trisubstituted by F and aryl can be    unsubstituted or monosubstituted by CF3;-   R7 is H, (C1-C4) alkyl, halogen, wherein alkyl is unsubstituted or    mono, di- or trisubstituted by F;-   R8 is H, F;    in all its stereoisomeric forms, enantiomeric forms and mixtures in    any ratio, and its physiologically acceptable salts and tautomeric    forms.

Another embodiment according to the invention are compounds of theformula 1, where

-   R1 is (C1-C4) alkyl, (C3-C6) cycloalkyl, phenyl, wherein alkyl can    be unsubstituted or mono, di- or tri substituted by F;-   R2 is H, F, C, O—(C1-C4) alkylene-H, wherein alkylene is    unsubstituted or mono, di- or trisubstituted by F;-   R3 is H;-   R4 is H;-   R5 is H, (C1-C4) alkyl;-   A is phenyl, thiophene, thiazole, pyridine;-   n is 1, 2;-   z is 1;-   R6 is (C1-C4) alkyl, F, Cl, O—(C0-C6) alkylene-H, phenyl, wherein    phenyl can be unsubstituted or monosubstituted by CF3;-   R7 is H, (C1-C4) alkyl, Cl, wherein alkyl is unsubstituted or mono,    di- or trisubstituted by F;-   R8 is H, F;    in all its stereoisomeric forms, enantiomeric forms and mixtures in    any ratio, and its physiologically acceptable salts and tautomeric    forms.

Another embodiment according to the invention are compounds of theformula 1, where

-   R1 is ethyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl, phenyl    or trifluoromethyl;-   R2, R3, R4, R5 are H, F, Cl, OCH3, OCH2CF3;-   A is phenyl;-   n is 1;-   z is 1;-   R6 is in ortho position and Cl, Br, or O(C1-C2)-alkyl;-   R7 is in para position and Cl, Br or CF3;-   R8 is H;    in all its stereoisomeric forms, enantiomeric forms and mixtures in    any ratio, and its physiologically acceptable salts and tautomeric    forms.

Another embodiment according to the invention are compounds of theformula 1, where

-   R1 is isopropyl;-   R2, R3, R4, R5 are H;-   A is phenyl;-   n is 1;-   z is 1;-   R6 is O(C1-C2)-alkyl and in ortho position-   R7 is in para position and Cl or CF3;-   R8 is H;    in all its stereoisomeric forms, enantiomeric forms and mixtures in    any ratio, and its physiologically acceptable salts and tautomeric    forms.

Another embodiment according to the invention are compounds of theformula 1, where

-   R1 is trifluoromethyl;-   R2, R3, R4, R5 are H;-   A is phenyl;-   n is 1;-   z is 1;-   R6 is O-ethyl and in ortho position-   R7 is in para position and Cl or CF3;-   R8 is H;    in all its stereoisomeric forms, enantiomeric forms and mixtures in    any ratio, and its physiologically acceptable salts and tautomeric    forms.

Another embodiment according to the invention are compounds of theformula 1, where

-   R1 is cyclohexyl;-   R2, R3, R4, R5 are H;-   A is phenyl;-   n is 1;-   z is 1;-   R6 is O-ethyl and in ortho position-   R7 is in para position and Cl or CF3,-   R8 is H    in all its stereoisomeric forms, enantiomeric forms and mixtures in    any ratio, and its physiologically acceptable salts and tautomeric    forms.

Another embodiment according to the invention are compounds of theformula 1, where

-   R1 is phenyl;-   R2, R3, R4, R5 are H;-   A is phenyl;-   n is 1;-   z is 1;-   R6 is O-ethyl and in ortho position-   R7 is in para position and Cl or CF3;-   R8 is H;    in all its stereoisomeric forms, enantiomeric forms and mixtures in    any ratio, and its physiologically acceptable salts and tautomeric    forms.

Another embodiment according to the invention are compounds of theformula 1, where

-   R1 is cyclopropyl;-   R2, R3, R4, R5 are H;-   A is phenyl;-   n is 1;-   z is 1;-   R6 is O-ethyl and in ortho position-   R7 is in para position and Cl or CF3;-   R8 is H;    in all its stereoisomeric forms, enantiomeric forms and mixtures in    any ratio, and its physiologically acceptable salts and tautomeric    forms.

Another embodiment according to the invention are compounds of theformula 1, where

-   R1 is isopropyl;-   R2, R3, R4, R5 are H;-   A is thiophene;-   n is 1;-   z is 1;-   R6 is O-ethyl and in ortho position;-   R7 is in para position and Cl or CF3;-   R8 is H;    in all its stereoisomeric forms, enantiomeric forms and mixtures in    any ratio, and its physiologically acceptable salts and tautomeric    forms.

Another embodiment according to the invention is the compounds:

-   2-Ethoxy-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide-   2-Ethoxy-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide    (Enantiomer 1)-   2-Ethoxy-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide    (Enantiomer 2)-   2-Ethoxy-4-trifluoromethyl-N-[5-(5-trifluoromethyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-benzamide-   4-Methyl-2-(4-trifluormethyl-phenyl)-thiazol-5-carbonsäure-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-amid-   4-Methyl-2-(4-trifluormethyl-phenyl)-thiazol-5-carbonsäure-[5-(5-cyclopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-amid-   2-Ethoxy-N—[(S)-7-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-4-trifluoromethyl-benzamide-   2-Ethoxi-N—[(R)-7-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-1,2,3,4-tetrahydro-naphthalene-2-yl]-4-trifluoromethyl-benzamide-   N-[5-Chloro-6-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-2-ethoxy-4-trifluoromethyl-benzamide-   2-Ethoxy-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-6-methoxy-indan-2-yl]-4-trifluoromethyl-benzamide-   3-Ethoxy-5-trifluoromethyl-thiophene-2-carboxylic acid    [5-chloro-6-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-amide-   3-Ethoxy-5-trifluoromethyl-thiophene-2-carboxylic acid    [5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-6-methoxy-indan-2-yl]-amide-   3-Ethoxy-5-trifluoromethyl-thiophene-2-carboxylic acid    [5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-amide-   2-Ethoxy-N-[2-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl]-4-trifluoromethyl-benzamide-   2-Chloro-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-5-trifluoromethyl-benzamide-   4-Chloro-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-2-methyl-benzamide-   2,3-Difluoro-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide-   2-Fluoro-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide-   4-Chloro-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-2-methoxi-benzamide-   2,4-Dichloro-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-benzamide-   2-Ethoxy-N-[5-fluoro-6-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide-   2-Ethoxy-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-1-methyl-indan-2-yl]-4-trifluoromethyl-benzamide-   2-Ethoxy-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-6-(2,2,2-trifluoro-ethoxy)-indan-2-yl]-4-trifluoromethyl-benzamide-   N-[5-(5-Cyclopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-2-ethoxy-4-trifluoromethyl-benzamide-   2-Ethoxy-N-[5-(5-phenyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide-   2-Ethoxy-N-[5-(5-cyclhexyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide-   3-Methoxy-pyridine-2-carboxylic acid    [5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-amide.

This invention also encompasses all combinations of preferred aspects ofthe invention described herein.

As used herein, the term alkyl is to be understood in the broadest senseto mean saturated hydrocarbon residues which can be linear, i.e.straight-chain, or branched. If not otherwise defined alkyl has 1 to 8carbon atoms. Examples of “—(C1-C8)-alkyl” are alkyl residues containing1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms are methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl or octyl, the n-isomers of all these residues,isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl,2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl,tert-butyl or tert-pentyl. The term “—(C0-C8)-alkyl” is a hydrocarbonresidue containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, in which theterm “—C0-alkyl” is a covalent bond. All these statements apply also tothe term alkylene.

All these statements also apply if an alkyl group occurs as asubstituent on another residue, for example in an alkyloxy residue, analkyloxycarbonyl residue or an arylalkyl residue.

If not otherwise defined, alkyl and alkylene are unsubstituted or mono,di- or trisubstituted independently of one another by suitable groupssuch as, for example: F, Cl, Br, I, CF3, NO2, CN, COOH, CO—O—(C0-C4)alkylene-(C6-C10) aryl, CO—O—(C1-C4) alkyl, CO—O—(C0-C4)alkylene-(C3-C13)cycloalkyl, CO—O—(C0-C4) alkylene-(C3-C15)heterocycle,CO—N((C0-C4) alkylene-H)—(C0-C4) alkylene-(C6-C10) aryl, CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene-H, CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl, CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene-(C3-C15) heterocycle, (C0-C4) alkylene-(C3-C6)cycloalkyl,(C0-C4) alkylene-(C6-C10)aryl, (C0-C4) alkylene-(C3-C15)heterocycle,(C2-C6)-alkenyl, (C2-C6)-alkynyl, O—(C0-C6)-alkyl, O—(C0-C4)alkylene-(C6-C10) aryl, O—(C0-C4) alkylene-(C3-C12)cycloalkyl, O—(C0-C4)alkylene-(C3-C15)heterocycle, O—CO—O—(C0-C4) alkylene-(C6-C10) aryl,O—CO—O—(C1-C4) alkyl, O—CO—O—(C0-C4) alkylene-(C3-C13)cycloalkyl,O—CO—O—(C0-C4) alkylene-(C3-C15)heterocycle, S—(C1-C4)alkyl, S—(C0-C4)alkylene-(C3-C13)cycloalkyl, S—(C0-C4) alkylene-(C6-C10) aryl, S—(C0-C4)alkylene-(C3-C15) heterocycle, SO—(C1-C4)alkyl, SO—(C0-C4)alkylene-(C3-C13)cycloalkyl, SO—(C0-C4) alkylene-(C6-C10) aryl,SO—(C0-C4) alkylene-(C3-C15) heterocycle, SO2-(C1-C4)alkyl, SO2-(C0-C4)alkylene-(C3-C13)cycloalkyl, SO2-(C0-C4) alkylene-(C6-C10) aryl,SO2-(C0-C4) alkylene-(C3-C15) heterocycle,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C10)aryl,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-H, SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle where thearyl ring or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H;N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, N((C0-C4)alkylene-H)—(C0-C4)alkylene-H)—(C1-C6)cycloalkyl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle,where the aryl ring or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, SO2-CH3, COOH,COO—(C1-C6)-alkyl, SF5, CONH2.

The term cycloalkyl is to be understood to mean saturated hydrocarboncycle containing from 3 to 13 carbon atoms in a mono- or bicyclic,fused, bridged or spirocyclic ring. Examples of (C3-C13)-cycloalkylcyclic alkyl residues are cycloalkyl residues containing 3, 4, 5, 6, 7,8, 9, 10, 11, 12 or 13 ring carbon atoms like cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl or cyclododecyl. The term cycloalkyl alsoincludes bicyclic groups in which any of the above cycloalkyl ring isfused to a benzene ring, for example indane and1,2,3,4-tetrahydronaphthalene.

If not otherwise defined cycloalkyl is unsubstituted or mono, di- ortrisubstituted independently of one another by suitable groups such as,for example: F, Cl, Br, I, CF3, NO2, CN, COOH, CO—O—(C0-C4)alkylene-(C6-C10) aryl, CO—O—(C1-C4) alkyl, CO—O—(C0-C4)alkylene-(C3-C13)cycloalkyl, CO—O—(C0-C4) alkylene-(C3-C15)heterocycle,CO—N((C0-C4) alkylene-H)—(C1-C6)alkylene-H, CO—N((C0-C4)alkylene-H)—(C1-C6)cycloalkyl, CON((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl, (C0-C4)alkylene-(C3-C6)cycloalkyl, (C3-C6)alkyl, (C2-C6)-alkenyl,(C2-C6)-alkynyl, (C0-C4) alkylene-(C6-C10)aryl, (C0-C4)alkylene-(C3-C15)heterocycle, O—(C0-C6)-alkyl, (C0-C4)alkylene-O—(C0-C4) alkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C3-C13)cycloalkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C6-C10)aryl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C3-C15)heterocycle, O—CO—O—(C0-C4) alkylene-(C6-C10) aryl,O—CO—O—(C1-C4) alkyl, O—CO—O—(C0-C4) alkylene-(C3-C13)cycloalkyl,O—CO—O—(C0-C4) alkylene-(C3-C15)heterocycle, O—CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene- (C6-C10) aryl, O—CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene-H, O—CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene- (C3-C13)cycloalkyl, O—CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene- (C3-C15) heterocycle, S—(C1-C4)alkyl, S—(C0-C4)alkylene-(C3-C13)cycloalkyl, S—(C0-C4) alkylene-(C6-C10) aryl, S—(C0-C4)alkylene-(C3-C15) heterocycle, SO—(C1-C4)alkyl, SO—(C0-C4)alkylene-(C3-C13)cycloalkyl, SO—(C0-C4) alkylene-(C6-C10) aryl,SO—(C0-C4) alkylene-(C3-C15) heterocycle, SO2-(C1-C4)alkyl, SO2-(C0-C4)alkylene-(C3-C13)cycloalkyl, SO2-(C0-C4) alkylene-(C6-C10) aryl,SO2-(C0-C4) alkylene-(C3-C15) heterocycle,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C10)aryl,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-H, SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, where thearyl ring or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H;N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, N((C0-C4)alkylene-H)—(C0-C4)alkylene-H)—(C1-C6)cycloalkyl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle,where the aryl or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H,SO2-CH3, COOH,COO—(C1-C6)-alkyl, SF5, CONH2.

The term “aryl” is understood to mean aromatic hydrocarbon ringcontaining from 6 to 14 carbon atoms in a mono- or bicyclic ring.Examples of (C6-C14)-aryl rings are phenyl, naphthyl, for example1-naphthyl and 2-naphthyl, biphenyl, for example 2-biphenylyl,3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl. Biphenyl rings,naphthyl ring and, in particular, phenyl ring are further embodiments ofaryl ring.

The terms heterocycle is understood to mean saturated(heterocycloalkyl), partly unsaturated (heterocycloalkenyl) orunsaturated (heteroaryl)hydrocarbon rings containing from 3 to 15 carbonatoms in a mono- or bicyclic, fused, bridged or spirocyclicring in which1 to 5 carbon atoms of the 3 to 15 ring carbon atoms are replaced byheteroatoms such as nitrogen, oxygen or sulfur in which further theheteroatoms can be oxidized, for example N═O, S═O, SO2. Examples ofheterocycles are acridinyl, azaindole (1H-pyrrolopyridinyl),azabenzimidazolyl, azaspirodecanyl, azepinyl, azetidinyl, aziridinyl,benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydrochinolinyl, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl,1,3-dioxolanyl, 1,3-dioxolenyl, 3,3-dioxo[1,3,4]oxathiazinyl,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuranyl, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isothiazolidinyl, isothiazolinyl,isoxazolyl, isoxazolinyl, isoxazol idinyl, 2-isoxazolinyl,ketopiperazinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2-oxa-thiepanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl,1,4-oxazepinyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl,oxazolinyl, oxazolyl, oxetanyl, oxocanyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl,pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl,tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl,1,3-thiazolyl, thiazolyl, thiazolidinyl, thiazolinyl, thienyl,thietanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

The heterocyclic rings are unsubstituted or mono-, di- or trisubstitutedby suitable groups such as, for example: F, Cl, Br, I, CF3, NO2, CN,COOH, CO—O—(C0-C4) alkylene-(C6-C10) aryl, CO—O—(C1-C4) alkyl,CO—O—(C0-C4) alkylene-(C3-C13)cycloalkyl, CO—O—(C0-C4)alkylene-(C3-C15)heterocycle, CO—N((C0-C4)alkylene-H)—(C1-C6)alkylene-H, CO—N((C0-C4)alkylene-H)—(C1-C6)cycloalkyl, CON((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl, (C0-C4)alkylene-(C3-C6)cycloalkyl, (C3-C6)alkyl, (C2-C6)-alkenyl,(C2-C6)-alkynyl, (C0-C4) alkylene-(C6-C10)aryl, (C0-C4)alkylene-(C3-C15)heterocycle, O—(C0-C6)-alkyl, (C0-C4)alkylene-O—(C0-C4) alkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C3-C13)cycloalkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C6-C10)aryl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C3-C15)heterocycle, O—CO—O—(C0-C4) alkylene-(C6-C10) aryl,O—CO—O—(C1-C4) alkyl, O—CO—O—(C0-C4) alkylene-(C3-C13)cycloalkyl,O—CO—O—(C0-C4) alkylene-(C3-C15)heterocycle, O—CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene- (C6-C10) aryl, O—CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene-H, O—CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene- (C3-C13)cycloalkyl, O—CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene- (C3-C15) heterocycle, S—(C1-C4)alkyl, S—(C0-C4)alkylene-(C3-C13)cycloalkyl, S—(C0-C4) alkylene-(C6-C10) aryl, S—(C0-C4)alkylene-(C3-C15) heterocycle, SO—(C1-C4)alkyl, SO—(C0-C4)alkylene-(C3-C13)cycloalkyl, SO—(C0-C4) alkylene-(C6-C10) aryl,SO—(C0-C4) alkylene-(C3-C15) heterocycle, SO2-(C1-C4)alkyl, SO2-(C0-C4)alkylene-(C3-C13)cycloalkyl, SO2-(C0-C4) alkylene-(C6-C10) aryl,SO2-(C0-C4) alkylene-(C3-C15) heterocycle,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C10)aryl,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-H, SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, where thearyl ring or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H,;

N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, N((C0-C4)alkylene-H)—(C0-C4)alkylene-H)—(C1-C6)cycloalkyl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle,where the aryl or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, SO2-CH3, COOH,COO—(C1-C6)-alkyl, SF5, CONH2.

The term “oxo-residue” or “═O” refers to residues such as carbonyl(—CO—), nitroso (—N═O), sulfinyl (—SO— or sulfonyl (—SO₂—).

Halogen is fluorine, chlorine, bromine or iodine.

Optically active carbon atoms present in the compounds of the formula Ican independently of each other have R configuration or S configuration.The compounds of the formula I can be present in the form of pureenantiomers or pure diastereomers or in the form of mixtures ofenantiomers and/or diastereomers, for example in the form of racemates.The present invention relates to pure enantiomers and mixtures ofenantiomers as well as to pure diastereomers and mixtures ofdiastereomers. The invention comprises mixtures of two or of more thantwo stereoisomers of the formula I and it comprises all ratios of thestereoisomers in the mixtures. In case the compounds of the formula Ican be present as E isomers or Z isomers (or cis isomers or transisomers) the invention relates both to pure E isomers and pure Z isomersand to E/Z mixtures in all ratios. The invention also comprises alltautomeric forms of the compounds of the formula 1.

Diastereomers, including E/Z isomers, can be separated into theindividual isomers, for example, by chromatography. Racemates can beseparated into the two enantiomers by customary methods, for example bychromatography on chiral phases or by resolution, for example bycrystallization of diastereomeric salts obtained with optically activeacids or bases. Stereochemically uniform compounds of the formula I canalso be obtained by employing stereochemically uniform startingmaterials or by using stereoselective reactions.

The compounds of the formula I may exist in the form of their racemates,racemic mixtures, pure enantiomers, diastereomers and mixtures ofdiastereomers as well in their tautomeric forms. The present inventionencompasses all these isomeric and tautomeric forms of the compounds ofthe formula 1. These isomeric forms can be obtained by known methodseven if not specifically described in some cases.

Pharmaceutically acceptable salts are, because their solubility in wateris greater than that of the initial or basic compounds, particularlysuitable for medical applications. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention aresalts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acid, and of organicacids such as, for example, acetic acid, benzenesulfonic, benzoic,citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonicand tartaric acid. Suitable pharmaceutically acceptable basic salts areammonium salts, alkali metal salts (such as sodium and potassium salts),alkaline earth metal salts (such as magnesium and calcium salts), andsalts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol),diethanolamine, lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion such as, for example,trifluoroacetate likewise belong within the framework of the inventionas useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications.

The term “physiologically functional derivative” used herein refers toany physiologically tolerated derivative of a compound of the formula Iof the invention, for example an ester, which on administration to amammal such as, for example, a human is able to form (directly orindirectly) a compound of the formula I or an active metabolite thereof.

Physiologically functional derivatives also include prodrugs of thecompounds of the invention, as described, for example, in H. Okada etal., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can bemetabolized in vivo to a compound of the invention. These prodrugs maythemselves be active or not.

The compounds of the invention may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds of the invention belong within theframework of the invention and are a further aspect of the invention.

All references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described above, and their salts,solvates and physiologically functional derivatives as described herein.

Use

This invention relates further to the use of compounds of the formula Iand their pharmaceutical compositions as PPAR ligands. The PPAR ligandsof the invention are suitable as modulators of PPAR activity.

Peroxisome proliferator-activated receptors (PPAR) are transcriptionfactors which can be activated by ligands and belong to the class ofnuclear hormone receptors. There are three PPAR isoforms, PPARalpha,PPARgamma and PPARdelta (identical to PPARbeta), which are encoded bydifferent genes (Peroxisome proliferator-activated receptor (PPAR):structure, mechanisms of activation and diverse functions: Motojima K.,Cell Struct Funct., 1993, 18(5), 267-77).

In humans, PPARgamma exists in three variants, PPARgamma₁, gamma₂, andgamma₃, which are the result of alternative use of promoters anddifferential mRNA splicing. Different PPARs have different tissuedistribution and modulate different physiological functions. The PPARsplay a key role in various aspects of the regulation of a large numberof genes, the products of which genes are directly or indirectlycrucially involved in lipid and carbohydrate metabolism. Thus, forexample, the PPARalpha receptor plays an important part in theregulation of fatty acid catabolism or lipoprotein metabolism in theliver, while PPARgamma is crucially involved for example in regulatingadipose cell differentiation. In addition, however, PPARs are alsoinvolved in the regulation of many other physiological processes,including those which are not directly connected with carbohydrate orlipid metabolism. The activity of different PPARs can be modulated byvarious fatty acids, fatty acid derivatives and synthetic compounds tovarying extents. For relevant reviews about functions, physiologicaleffects and pathophysiology, see: Berger, J. et al., Annu. Rev. Med.,2002, 53, 409-435; Wilson, T. et al., J. Med. Chem., 2000, 43 (4),527-550; Kliewer, S. et al., Recent Prog Horm Res., 2001, 56, 239-63;Moller, D. E. and Berger, J. P., Int J Obes Relat Metab Disord., 2003,27 Suppl 3, 17-21; Ram, V. J., Drugs Today, 2003, 39(8), 609-32).

Among the three PPAR-isoforms the physiological functions of PPARdeltahave long remained an enigma. The first proposed pharmacological rolefor PPARdelta has been the regulation of cholesterol homeostasis. It wasshown that the somewhat selective PPARdelta ligand L-165041 raisesplasma cholesterol in a diabetic animal model (Berger J. et al., J.Biol. Chem., 1999, 274, 6718-6725; Leibowitz M. D. et al., FEBS Lett.,2000, 473(3), 333-336). In obese, insulin resistant rhesus monkeys, thepotent and selective PPARdelta ligand GW501516 raises HDL-cholesterol,decreases plasma LDL-cholesterol, triglycerides and insulin levels(Oliver, W. et al., Proc. Natl. Acad. Sci., 2001, 98, 5306-5311). Thedual PPARdelta/PPARalpha agonist YM-16638 significantly lowers plasmalipids in rhesus and cynomolgus monkeys (Goto, S. et al., Br. J. Pharm.,1996, 118, 174-178) and acts in a similar manner in two weeks clinicaltrials in healthy volunteers (Shimokawa, T. et al., Drug Dev. Res.,1996, 38, 86-92). More recent publications underline that PPARdelta isan important target for the treatment of dyslipidemia, insulinresistance, type 2 diabetes, atherosclerosis and syndrom X (Wang, Y-X.et al., Cell, 2003, 113, 159-170; Luquet, S. et al., FASEB J., 2003, 17,209-226; Tanaka, T. et al., PNAS, 2003, 100, 15924-15929; Holst, D. etal., BioChem. Biophys. Acta, 2003, 1633, 43-50; Dressel, U. et al., Mol.Endocrin., 2003, 17, 2477-2493; Lee, C. H. et al., Science, 2003, 302,453-457). Besides its actions as a regulator of the lipid-, glucose- andcholesterol-metabolism PPARdelta is known to play a role in embryonicdevelopment, implantation and bone formation (Lim, H. and Dey, S. K.,Trends Endocrinol Metab., 2000, 11(4), 137-42; Ding, N. Z. et al., MolReprod Dev., 2003, 66(3), 218-24; Mano, H. et al., J Biol. Chem., 2000,275(11), 8126-32).

Numerous publications demonstrate that PPARdelta is triggeringproliferation and differentiation of keratinocytes which points to itsrole in skin disorders and wound healing (Di-Poi, N. et al., J SteroidBiochem Mol. Biol., 2003, 85(2-5), 257-65; Tan, N. S. et al., Am J ClinDermatol., 2003, 4(8), 523-30; Wahli, W., Swiss Med. Wkly., 2002,132(7-8), 83-91).

PPARdelta appears to be significantly expressed in the CNS; however muchof its function there still remains undiscovered. Of singular interesthowever, is the discovery that PPARdelta was expressed in rodentoligodendrocytes, the major lipid producing cells of the CNS (J.Granneman, et al., J. Neurosci. Res., 1998, 51, 563-573). Moreover, itwas also found that a PPARdelta selective agonist was found tosignificantly increase oligodendroglial myelin gene expression andmyelin sheath diameter in mouse cultures (I. Saluja et al., Glia, 2001,33, 194-204). Thus, PPARdelta activators may be of use for the treatmentof demyelinating and dysmyelinating diseases. The use of peroxisomeproliferator activated receptor delta agonists for the treatment of MSand other demyelinating diseases can be shown as described inWO2005/097098.

Demyelinating conditions are manifested in loss of myelin—the multipledense layers of lipids and protein which cover many nerve fibers. Theselayers are provided by oligodendroglia in the central nervous system(CNS), and Schwann cells in the peripheral nervous system (PNS). Inpatients with demyelinating conditions, demyelination may beirreversible; it is usually accompanied or followed by axonaldegeneration, and often by cellular degeneration. Demyelination canoccur as a result of neuronal damage or damage to the myelinitself—whether due to aberrant immune responses, local injury, ischemia,metabolic disorders, toxic agents, or viral infections (Prineas andMcDonald, Demyelinating Diseases. In Greenfield's Neuropathology,6.sup.th ed. (Edward Arnold: New York, 1997) 813-811, Beers and Berkow,eds., The Merck Manual of Diagnosis and Therapy, 17.sup.th ed.(Whitehouse Station, N.J.: Merck Research Laboratories, 1999) 1299,1437, 1473-76, 1483).

Central demyelination (demyelination of the CNS) occurs in severalconditions, often of uncertain etiology, that have come to be known asthe primary demyelinating diseases. Of these, multiple sclerosis (MS) isthe most prevalent. Other primary demyelinating diseases includeadrenoleukodystrophy (ALD), adrenomyeloneuropathy, AIDS-vacuolarmyelopathy, HTLV-associated myelopathy, Leber's hereditary opticatrophy, progressive multifocal leukoencephalopathy (PML), subacutesclerosing panencephalitis, Guillian-Barre syndrome and tropical spasticparaparesis. In addition, there are acute conditions in whichdemyelination can occur in the CNS, e.g., acute disseminatedencephalomyelitis (ADEM) and acute viral encephalitis. Furthermore,acute transverse myelitis, a syndrome in which an acute spinal cordtransection of unknown cause affects both gray and white matter in oneor more adjacent thoracic segments, can also result in demyelination.Also, disorders in which myelin forming glial cells are damagedincluding spinal cord injuries, neuropathies and nerve injury.

The present invention relates to compounds of the formula I suitable formodulating the activity of PPARs, especially the activity of PPARdeltaand PPARalpha. Depending on the modulation profile, the compounds of theformula I are suitable for the treatment, control and prophylaxis of theindications described hereinafter, and for a number of otherpharmaceutical applications connected thereto (see, for example, Berger,J., et al., Annu. Rev. Med., 2002, 53, 409-435; Wilson, T. et al., J.Med. Chem., 2000, 43(4), 527-550; Kliewer, S. et al., Recent Prog HormRes., 2001, 56, 239-63; Fruchart, J. C. et al., 2001, PharmacologicalResearch, 44(5), 345-52; Kersten, S. et al., Nature, 2000, 405, 421-424;Torra, I. P. et al., Curr Opin Lipidol, 2001, 12, 245-254).

Compounds of this type are particularly suitable for the treatmentand/or prevention of:

-   1.—Disorders of fatty acid metabolism and glucose utilization    disorders.    -   Disorders in which insulin resistance is involved-   2. Diabetes mellitus, especially type 2 diabetes, including the    prevention of the sequelae associated therewith.    -   Particular aspects in this connection are    -   hyperglycemia,    -   improvement in insulin resistance,    -   improvement in glucose tolerance,    -   protection of the pancreatic β cells    -   prevention of macro- and microvascular disorders-   3. Dyslipidemias and their sequelae such as, for example,    atherosclerosis, coronary heart disease, cerebrovascular disorders    etc, especially those (but not restricted thereto) which are    characterized by one or more of the following factors: high plasma    triglyceride concentrations, high postprandial plasma triglyceride    -   concentrations,    -   low HDL cholesterol concentrations    -   low ApoA lipoprotein concentrations    -   high LDL cholesterol concentrations    -   small dense LDL cholesterol particles    -   high ApoB lipoprotein concentrations-   4. Various other conditions which may be associated with the    metabolic syndrome, such as:    -   obesity (excess weight), including central obesity    -   thromboses, hypercoagulable and prothrombotic states (arterial        and venous)    -   high blood pressure    -   heart failure such as, for example (but not restricted thereto),        following myocardial infarction, hypertensive heart disease or        cardiomyopathy-   5. Disorders or conditions in which inflammatory reactions are    involved:    -   atherosclerosis such as, for example (but not restricted        thereto), coronary sclerosis including angina pectoris or        myocardial infarction, stroke    -   vascular restenosis or reocclusion    -   chronic inflammatory bowel diseases such as, for example,        Crohn's disease and ulcerative colitis    -   asthma    -   lupus erythematosus (LE) or inflammatory rheumatic disorders        such as, for example, rheumatoid arthritis    -   other inflammatory states-   6. Disorders of cell cycle or cell differentiation processes:    -   adipose cell tumors    -   lipomatous carcinomas such as, for example, liposarcomas    -   solid tumors and neoplasms such as, for example (but not        restricted thereto), carcinomas of the gastrointestinal tract,        of the liver, of the biliary tract and of the pancreas,        endocrine tumors, carcinomas of the lungs, of the kidneys and        the urinary tract, of the genital tract, prostate carcinomas etc    -   acute and chronic myeloproliferative disorders and lymphomas    -   angiogenesis-   7. Demyelinating and other neurodegenerative disorders of the    central and peripheral nervous systems including:    -   Alzheimer's disease    -   multiple sclerosis    -   Parkinson's disease    -   adrenoleukodystrophy (ALD)    -   adrenomyeloneuropathy    -   AIDS-vacuolar myelopathy    -   HTLV-associated myelopathy    -   Leber's hereditary optic atrophy    -   progressive multifocal leukoencephalopathy (PML)    -   subacute sclerosing panencephalitis    -   Guillian-Barre syndrome    -   tropical spastic paraparesis    -   acute disseminated encephalomyelitis (ADEM)    -   acute viral encephalitis    -   acute transverse myelitis    -   spinal cord and brain trauma    -   Charcot-Marie-Tooth disease-   8. Skin disorders and/or disorders of wound healing processes:    -   erythemato-squamous dermatoses such as, for example, psoriasis    -   acne vulgaris    -   other skin disorders and dermatological conditions which are        modulated by PPAR    -   eczemas and neurodermitis    -   dermatitis such as, for example, seborrheic dermatitis or        photodermatitis    -   keratitis and keratoses such as, for example, seborrheic        keratoses, senile keratoses, actinic keratosis, photo-induced        keratoses or keratosis follicularis    -   keloids and keloid prophylaxis    -   warts, including condylomata or condylomata acuminata    -   human papilloma viral (HPV) infections such as, for example,        venereal papillomata, viral warts such as, for example,        molluscum contagiosum, leukoplakia    -   papular dermatoses such as, for example, Lichen planus    -   skin cancer such as, for example, basal-cell carcinomas,        melanomas or cutaneous T-cell lymphomas    -   localized benign epidermal tumors such as, for example,        keratoderma, epidermal naevi    -   chilblains    -   wound healing-   9. Other disorders    -   high blood pressure    -   pancreatitis    -   syndrome X    -   polycystic ovary syndrome (PCOS)    -   asthma    -   osteoarthritis    -   lupus erythematosus (LE) or inflammatory rheumatic disorders        such as, for example, rheumatoid arthritis    -   vasculitis    -   wasting (cachexia)    -   gout    -   ischemia/reperfusion syndrome    -   acute respiratory distress syndrome (ARDS)        Formulations

The amount of a compound of formula I necessary to achieve the desiredbiological effect depends on a number of factors, for example thespecific compound chosen, the intended use, the mode of administrationand the clinical condition of the patient. The daily dose is generallyin the range from 0.001 mg to 100 mg (typically from 0.01 mg to 50 mg)per day and per kilogram of bodyweight, for example 0.1-10 mg/kg/day. Anintravenous dose may be, for example, in the range from 0.001 mg to 1.0mg/kg, which can suitably be administered as infusion of 10 ng to 100 ngper kilogram and per minute. Suitable infusion solutions for thesepurposes may contain, for example, from 0.1 ng to 10 mg, typically from1 ng to 10 mg, per milliliter. Single doses may contain, for example,from 1 mg to 10 g of the active ingredient. Thus, ampules for injectionsmay contain, for example, from 1 mg to 100 mg, and single-doseformulations which can be administered orally, such as, for example,capsules or tablets, may contain, for example, from 0.05 to 1000 mg,typically from 0.5 to 600 mg. For the therapy of the abovementionedconditions, the compounds of formula I may be used as the compounditself, but they are preferably in the form of a pharmaceuticalcomposition with an acceptable carrier. The carrier must, of course, beacceptable in the sense that it is compatible with the other ingredientsof the composition and is not harmful for the patient's health. Thecarrier may be a solid or a liquid or both and is preferably formulatedwith the compound as a single dose, for example as a tablet, which maycontain from 0.05% to 95% by weight of the active ingredient. Otherpharmaceutically active substances may likewise be present, includingother compounds of formula 1. The pharmaceutical compositions of theinvention can be produced by one of the known pharmaceutical methods,which essentially consist of mixing the ingredients withpharmacologically acceptable carriers and/or excipients.

Pharmaceutical compositions of the invention are those suitable fororal, rectal, topical, peroral (for example sublingual) and parenteral(for example subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula Iused in each case. Coated formulations and coated slow-releaseformulations also belong within the framework of the invention.Preference is given to acid- and gastric juice-resistant formulations.Suitable coatings resistant to gastric juice comprise cellulose acetatephthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

Suitable pharmaceutical preparations for oral administration may be inthe form of separate units such as, for example, capsules, cachets,suckable tablets or tablets, each of which contain a defined amount ofthe compound of formula I; as powders or granules, as solution orsuspension in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method which includes a step inwhich the active ingredient and the carrier (which may consist of one ormore additional ingredients) are brought into contact. The compositionsare generally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. Thus, for example, a tabletcan be produced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one (ormore) surface-active/dispersing agent(s) in a suitable machine. Moldedtablets can be produced by molding the compound, which is in powder formand is moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration comprise suckable tablets which contain a compound offormula I with a flavoring, normally sucrose and gum arabic ortragacanth, and pastilles which comprise the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administrationcomprise preferably sterile aqueous preparations of a compound offormula 1, which are preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration may also take place by subcutaneous,intramuscular or intradermal injection. These preparations canpreferably be produced by mixing the compound with water and making theresulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain from 0.1 to 5% by weightof the active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of the formula I with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aerosolor oil. Carriers which can be used are petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingredient is generally present in a concentration of from0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses can be in the form of single plasterswhich are suitable for long-term close contact with the patient'sepidermis. Such plasters suitably contain the active ingredient in anaqueous solution which is buffered where appropriate, dissolved and/ordispersed in an adhesive or dispersed in a polymer. A suitable activeingredient concentration is about 1% to 35%, preferably about 3% to 15%.A particular possibility is for the active ingredient to be released byelectrotransport or iontophoresis as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

The compounds of the formula I are distinguished by favorable effects onmetabolic disorders. They beneficially influence lipid and sugarmetabolism, in particular they lower the triglyceride level and aresuitable for the prevention and treatment of type II diabetes andatherosclerosis and the diverse sequalae thereof.

Combinations with Other Medicaments

The compounds of the invention can be administered alone or incombination with one or more further pharmacologically activesubstances. In particular, the compounds of the invention can beadministered in combination with active ingredients having a similarpharmacological action. For example, they can be administered incombination with active ingredients which have favorable effects onmetabolic disturbances or disorders frequently associated therewith.Examples of such medicaments are

-   -   1. medicaments which lower blood glucose, antidiabetics,    -   2. active ingredients for the treatment of dyslipidemias,    -   3. antiatherosclerotic medicaments,    -   4. antiobesity agents,    -   5. antiinflammatory active ingredients    -   6. active ingredients for the treatment of malignant tumors    -   7. antithrombotic active ingredients    -   8. active ingredients for the treatment of high blood pressure    -   9. active ingredients for the treatment of heart failure and    -   10. active ingredients for the treatment and/or prevention of        complications caused by diabetes or associated with diabetes.    -   11. active ingredients for the treatment of neurodegenerative        diseases    -   12. active ingredients for the treatment of disorders of the        central nervous system    -   13. active ingredients for the treatment of drug, nicotine and        alcohol addiction    -   14. analgesics

They can be combined with the compounds of the invention of the formulaI in particular for a synergistic enhancement of activity.Administration of the active ingredient combination can take placeeither by separate administration of the active ingredients to thepatient or in the form of combination products in which a plurality ofactive ingredients are present in one pharmaceutical preparation.

Particularly suitable further active ingredients for the combinationpreparations are:

All antidiabetics mentioned in the Rote Liste 2006, Chapter 12; allslimming agents/appetite suppressants mentioned in the Rote Liste 2006,Chapter 1; all lipid-lowering agents mentioned in the Rote Liste 2006,Chapter 58. They can be combined with the compound of the formula Iaccording to the invention in particular for a synergistic enhancementof activity. The active compound combination can be administered eitherby separate administration of the active compounds to the patient or inthe form of combination preparations in which a plurality of activecompounds are present in a pharmaceutical preparation. Most of theactive compounds listed below are disclosed in USP Dictionary of USANand International Drug Names, US Pharmacopeia, Rockville 2001.

Antidiabetics include insulin and insulin derivatives, such as, forexample, Lantus® (see www.lantus.com) or HMR 1964 or those described inWO2005005477 (Novo Nordisk), fast-acting insulins (see U.S. Pat. No.6,221,633), inhalable insulins, such as, for example, Exubera® or oralinsulins, such as, for example, IN-105 (Nobex) or Oral-lyn™ (GenerexBiotechnology), GLP-1 derivatives, such as, for example, Exenatide,Liraglutide or those disclosed in WO 98/08871 or WO2005027978 by NovoNordisk A/S, in WO 01/04156 by Zealand or in WO 00/34331 byBeaufour-Ipsen, pramlintide acetate (Symlin; Amylin Pharmaceuticals),and also orally effective hypoglycemic active ingredients.

The active compounds preferably include

-   sulfonylureas,-   biguanidines,-   meglitinides,-   oxadiazolidinediones,-   thiazolidinediones,-   glucosidase inhibitors,-   inhibitors of glycogen phosphorylase,-   glucagon antagonists,-   glucokinase activators,-   inhibitors of fructose-1,6-bisphosphatase,-   modulators of the glucose transporter 4 (GLUT4),-   inhibitors of glutamine:fructose-6-phosphate amidotransferase    (GFAT),-   GLP-1 agonists,-   potassium channel openers, such as, for example, those disclosed in    WO 97/26265 and WO 99/03861 by Novo Nordisk A/S,-   inhibitors of dipeptidylpeptidase IV (DPP-IV),-   insulin sensitizers,-   inhibitors of liver enzymes involved in the stimulation of    gluconeogenesis and/or-   glycogenolysis,-   modulators of glucose uptake, glucose transport and glucose    backresorption, inhibitors of 11β-HSD1,-   inhibitors of protein tyrosine phosphatase 1B (PTP1B),-   modulators of the sodium/glucose cotransporter 1 or 2 (SGLT1,    SGLT2),-   compounds which alter lipid metabolism, such as antihyperlipidemic    active ingredients and antilipidemic active ingredients,-   compounds which reduce food intake or food absorption,-   compounds which increase thermogenesis,-   PPAR and RXR modulators and-   active ingredients which act on the ATP-dependent potassium channel    of the beta cells.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a HMGCoA reductase inhibitor, such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, rosuvastatin or L-659699.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a cholesterol resorption inhibitor,such as, for example, ezetimibe, tiqueside, pamaqueside, FM-VP4(sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech,WO2005042692), MD-0727 (Microbia Inc., WO2005021497) or with compoundsas described in WO2002066464 (Kotobuki Pharmaceutical Co. Ltd.),WO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZenecaAB).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR gamma agonist, such as, forexample, rosiglitazone, pioglitazone, JTT-501, GI 262570, R-483 orCS-011 (rivoglitazone).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR alpha agonist, such as, forexample, GW9578, GW-590735, K-111, LY-674, KRP-101 or DRF-10945.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a mixed PPAR alpha/gamma agonist, suchas, for example, muraglitazar, tesaglitazar, naveglitazar, LY-510929,ONO-5129, E-3030 or as described in WO0/64888, WO0/64876, WO03/020269,WO2004075891, WO2004076402, WO2004075815, WO2004076447, WO2004076428,WO2004076401, WO2004076426, WO2004076427, WO2006018118, WO2006018115,and WO2006018116 or in J. P. Berger et al., TRENDS in PharmacologicalSciences 28(5), 244-251, 2005.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR delta agonist, such as, forexample, GW-501516 or as described in WO2005097762, WO2005097786,WO2005097763, and WO2006029699.

In one embodiment of the invention, the compound of the formula I isadministered in combination with metaglidasen or with MBX-2044 or otherpartial PPAR gamma agonists/antagonists.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a fibrate, such as, for example,fenofibrate, clofibrate or bezafibrate.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an MTP inhibitor, such as, for example,implitapide, BMS-201038, R-103757 or those described in WO2005085226.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a CETP inhibitor, such as, for example,torcetrapib or JTT-705.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a bile acid resorption inhibitor (see,for example, U.S. Pat. Nos. 6,245,744, 6,221,897 or WO0/61568), such as,for example, HMR 1741 or those described in DE 10 2005 033099.1 and DE10 2005 033100.9.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a polymeric bile acid adsorber, suchas, for example, cholestyramine or colesevelam.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an LDL receptor inducer (see U.S. Pat.No. 6,342,512), such as, for example, HMR1171, HMR1586 or thosedescribed in WO2005097738.

In one embodiment, the compound of the formula I is administered incombination with Omacor® (omega-3 fatty acids; highly concentrated ethylesters of eicosapentaenoic acid and docosahexaenoic acid).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ACAT inhibitor, such as, forexample, avasimibe.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an antioxidant, such as, for example,OPC-14117, probucol, tocopherol, ascorbic acid, β-carotene or selenium.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a vitamin, such as, for example,vitamin B6 or vitamin B12.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein lipase modulator, suchas, for example, ibrolipim (NO-1886).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ATP-citrate lyase inhibitor, suchas, for example, SB-204990.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a squalene synthetase inhibitor, suchas, for example, BMS-188494 or as described in WO2005077907.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein(a) antagonist, such as,for example, gemcabene (Cl-1027).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an HM74A receptor agonists, such as,for example, nicotinic acid.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipase inhibitor, such as, forexample, orlistat or cetilistat (ATL-962).

In one embodiment of the invention, the compound of the formula I isadministered in combination with insulin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a sulfonylurea, such as, for example,tolbutamide, glibenclamide, glipizide or glimepiride.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a biguanide, such as, for example,metformin.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a meglitinide, such as, for example,repaglinide or nateglinide.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a thiazolidinedione, such as, forexample, troglitazone, ciglitazone, pioglitazone, rosiglitazone or thecompounds disclosed in WO 97/41097 by Dr. Reddy's Research Foundation,in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an α-glucosidase inhibitor, such as,for example, miglitol or acarbose.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an active ingredient which acts on theATP-dependent potassium channel of the beta cells, such as, for example,tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment of the invention, the compound of the formula I isadministered in combination with more than one of the compoundsmentioned above, for example in combination with a sulfonylurea andmetformin, a sulfonylurea and acarbose, repaglinide and metformin,insulin and a sulfonylurea, insulin and metformin, insulin andtroglitazone, insulin and lovastatin, etc.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of glycogen phosphorylase,such as, for example, PSN-357 or FR-258900 or those described inWO2003084922, WO2004007455, WO2005073229-31 or WO2005067932.

In one embodiment of the invention, the compound of the formula I isadministered in combination with glucagon receptor antagonists, such as,for example, A-770077, NNC-25-2504 or such as in WO2004100875 orWO2005065680.

In one embodiment of the invention, the compound of the formula I isadministered in combination with activators of glucokinase, such as, forexample, RO-4389620, LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50or those described, for example, by Prosidion in WO2004072031,WO2004072066, WO 05103021 or WO 06016178, by Roche in WO 00058293, WO00183465, WO 00183478, WO 00185706, WO 00185707, WO 01044216, GB02385328, WO 02008209, WO 02014312, WO 0246173, WO 0248106, DE 10259786,WO 03095438, U.S. Pat. No. 4,067,939 or WO 04052869, by Novo Nordisk inEP 1532980, WO 03055482, WO 04002481, WO 05049019, WO 05066145 or WO05123132, by Merck/Banyu in WO 03080585, WO03097824, WO 04081001, WO05063738 or WO 05090332, by Eli Lilly in WO 04063194, or by Astra Zenecain WO 01020327, WO 03000262, WO 03000267, WO 03015774, WO 04045614, WO04046139, WO 05044801, WO 05054200, WO 05054233, WO 05056530, WO05080359, WO 05080360 or WO 05121110.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of gluconeogenesis, suchas, for example, FR-225654.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors offructose-1,6-bisphosphatase (FBPase), such as, for example, CS-917.

In one embodiment of the invention, the compound of the formula I isadministered in combination with modulators of the glucose transporter 4(GLUT4), such as, for example, KST-48 (D.-O. Lee et al.:Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004)).

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors ofglutamine:fructose-6-phosphate amidotransferase (GFAT), as described,for example, in WO2004101528.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of dipeptidylpeptidase IV(DPP-IV), such as, for example, vildagliptin (LAF-237), sitagliptin(MK-0431), saxagliptin ((BMS-477118), GSK-823093, PSN-9301, SYR-322,SYR-619, TA-6666, TS-021, GRC-8200, GW-825964× or as described inWO2003074500, WO2003106456, WO200450658, WO2005058901, WO2005012312,WO2005/012308, PCT/EP2005/007821, PCT/EP2005/008005, PCT/EP2005/008002,PCT/EP2005/008004, PCT/EP2005/008283, DE 10 2005 012874.2 or DE 10 2005012873.4.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of 11-beta-hydroxysteroiddehydrogenase-1 (11β-HSD1), such as, for example, BVT-2733 or thosedescribed, for example, in WO200190090-94, WO200343999, WO2004112782,WO200344000, WO200344009, WO2004112779, WO2004113310, WO2004103980,WO2004112784, WO2003065983, WO2003104207, WO2003104208, WO2004106294,WO2004011410, WO2004033427, WO2004041264, WO2004037251, WO2004056744,WO2004065351, WO2004089367, WO2004089380, WO2004089470-71, WO2004089896,WO2005016877 or WO2005097759.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of protein tyrosinephosphatase 1B (PTP1B), as described, for example, in WO200119830-31,WO200117516, WO2004506446, WO2005012295, PCT/EP2005/005311,PCT/EP2005/005321, PCT/EP2005/007151, PCT/EP2005/or DE 10 2004 060542.4.

In one embodiment of the invention, the compound of the formula I isadministered in combination with modulators of the sodium/glucosecotransporter 1 or 2 (SGLT1, SGLT2), such as, for example, KGA-2727,T-1095 and SGL-0010 or as described, for example, in WO2004007517,WO200452903, WO200452902, WO2005121161, WO2005085237, JP2004359630 or byA. L. Handlon in Expert Opin. Ther. Patents (2005) 15(11), 1531-1540.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of hormone-sensitive lipase(HSL), such as those described, for example, in WO01/17981, WO01/66531,WO2004035550, WO2005073199 or WO03/051842.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of acetyl-CoA carboxylase(ACC) such as those described, for example, in WO199946262, WO200372197,WO2003072197 or WO2005044814.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of phosphoenolpyruvatecarboxykinase (PEPCK), such as those described, for example, inWO2004074288.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of glycogen synthasekinase-3 beta (GSK-3 beta), such as those described, for example, inUS2005222220, WO2004046117, WO2005085230, WO2005111018, WO2003078403,WO2004022544, WO2003106410, WO2005058908, US2005038023, WO2005009997,US2005026984, WO2005000836, WO2004106343, EP1460075, WO2004014910,WO2003076442, WO2005087727 or WO2004046117.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of protein kinase C beta(PKC beta), such as, for example, ruboxistaurin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an endothelin-A receptor antagonist,such as, for example, avosentan (SPP-301).

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of “I-kappaB kinase” (IKKinhibitors), such as those described, for example, in WO2001000610,WO2001030774, WO2004022553 or WO2005097129.

In one embodiment of the invention, the compound of the formula I isadministered in combination with modulators of the glucocorticoidreceptor as described, for example, in WO2005090336.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with CART modulators (see“Cocaine-amphetamine-regulated transcript influences energy metabolism,anxiety and gastric emptying in mice” Asakawa, A. et al.: Hormone andMetabolic Research (2001), 33(9), 554-558); NPY antagonists such as, forexample,{4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl}naphthalene-1-sulfonamidehydrochloride (CGP 71683A); peptide YY 3-36 (PYY3-36) or analogouscompounds, such as, for example, CJC-1682 (PYY3-36 conjugated with humanserum albumin via Cys34), CJC-1643 (derivative of PYY3-36 whichconjugates in vivo to serum albumin) or those described in WO2005080424;

cannabinoid receptor 1 antagonists, such as, for example, rimonabant,SR147778 or those described, for example, in EP 0656354, WO 00/15609, WO02/076949, WO2005080345, WO2005080328, WO2005080343, WO2005075450,WO2005080357, WO200170700, WO2003026647-48, WO200302776, WO2003040107,WO2003007887, WO2003027069, U.S. Pat. No. 6,509,367, WO200132663,WO2003086288, WO2003087037, WO2004048317, WO2004058145, WO2003084930,WO2003084943, WO2004058744, WO2004013120, WO2004029204, WO2004035566,WO2004058249, WO2004058255, WO2004058727, WO2004069838, US20040214837,US20040214855, US20040214856, WO2004096209, WO2004096763, WO2004096794,WO2005000809, WO2004099157, US20040266845, WO2004110453, WO2004108728,WO2004000817, WO2005000820, US20050009870, WO200500974, WO2004111033-34,WO200411038-39, WO2005016286, WO2005007111, WO2005007628, US20050054679,WO2005027837, WO2005028456, WO2005063761-62, WO2005061509 orWO2005077897; MC4 agonists (for example[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-1-amino-1,2,3,4-tetrahydro-naphthalene-2-carboxamide;(WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764,CHIR-785, PT-141 or those described in WO2005060985, WO2005009950,WO2004087159, WO2004078717, WO2004078716, WO2004024720, US20050124652,WO2005051391, WO2004112793, WOUS20050222014, US20050176728,US20050164914, US20050124636, US20050130988, US20040167201,WO2004005324, WO2004037797, WO2005042516, WO2005040109, WO2005030797,US20040224901, WO200501921, WO200509184, WO2005000339, EP1460069,WO2005047253, WO2005047251, EP1538159, WO2004072076, WO2004072077 orWO2006024390; orexin receptor antagonists (for example1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride(SB-334867-A) or those described, for example, in WO200196302,WO200185693, WO2004085403 or WO2005075458); histamine H3 receptoragonists (for example3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-propan-1-oneoxalic acid salt (WO 00/63208) or those described in WO200064884,WO2005082893);

CRF antagonists (for example[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585));

CRF BP antagonists (for example urocortin);

urocortin agonists;

β3 agonists (such as, for example,1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanolhydrochloride (WO 01/83451));

MSH (melanocyte-stimulating hormone) agonists;

MCH (melanin-concentrating hormone) receptor antagonists (such as, forexample, NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71,GW-803430 or those compounds described in WO2003/15769, WO2005085200,WO2005019240, WO2004011438, WO2004012648, WO2003015769, WO2004072025,WO2005070898, WO2005070925, WO2006018280, WO2006018279, WO2004039780,WO2003033476, WO2002006245, WO2002002744, WO2003004027 or FR2868780);

CCK-A agonists (such as, for example,{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525), SR-146131 (WO 0244150) orSSR-125180);

serotonin reuptake inhibitors (for example dexfenfluramine);

mixed serotonin- and noradrenergic compounds (for example WO 00/71549);5-HT receptor agonists, for example 1-(3-ethylbenzofuran-7-yl)piperazineoxalic acid salt (WO 01/09111);

5-HT2C receptor agonists (such as, for example, APD-356, BVT-933 orthose described in WO200077010, WO20077001-02, WO2005019180,WO2003064423, WO200242304 or WO2005082859);

5-HT6 receptor antagonists, such as described, for example, inWO2005058858; bombesin receptor agonists (BRS-3 agonists);

galanin receptor antagonists;

growth hormone (for example human growth hormone or AOD-9604);

growth hormone releasing compounds (tert-butyl6-benzyloxy-1-(2-diisopropylamino-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate(WO 01/85695)); growth hormone secretagog receptor antagonists (ghrelinantagonists) such as, for example, A-778193 or those described inWO2005030734;

TRH agonists (see, for example, EP 0 462 884);

uncoupling protein 2 or 3 modulators;

leptin agonists (see for example Lee, Daniel W.; Leinung, Matthew C.;Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as apotential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881);

DA agonists (bromocriptine or Doprexin);

lipase/amylase inhibitors (as described, for example, in WO 00/40569);

inhibitors of diacylglycerol O-acyltransferases (DGATs) such asdescribed, for example, in US2004/0224997, WO2004094618, WO200058491,WO2005044250, WO2005072740, JP2005206492 or WO2005013907;

inhibitors of fatty acid synthase (FAS) such as, for example, C75 orthose described in WO2004005277;

oxyntomodulin;

oleoyl-estrone

or thyroid hormone receptor agonists, such as, for example, KB-2115 orthose described in WO20058279, WO200172692, WO200194293, WO2003084915,WO2004018421 or WO2005092316.

In one embodiment of the invention, the further active ingredient isleptin; see for example “Perspectives in the therapeutic use of leptin”,Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinionon Pharmacotherapy (2001), 2(10), 1615-1622.

In one embodiment of the invention, the further active ingredient isdexamphetamine or amphetamine.

In one embodiment of the invention, the further active ingredient isfenfluramine or dexfenfluramine.

In another embodiment of the invention, the further active ingredient issibutramine.

In one embodiment of the invention, the further active ingredient ismazindol or phentermine.

In one embodiment, the compounds of the formula I are administered incombination with bulking agents, preferably insoluble bulking agents(see, for example, carob/Caromax® (Zunft H J; et al., Carob pulppreparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY(2001 September-October), 18(5), 230-6). Caromax is a carob-containingproduct from Nutrinova, Nutrition Specialties & Food Ingredients GmbH,Industriepark Hochst, 65926 Frankfurt/Main). Combination with Caromax®is possible in one preparation or by separate administration ofcompounds of the formula I and Caromax®. Caromax® can in this connectionalso be administered in the form of food products such as, for example,in bakery products or muesli bars.

In one embodiment of the invention, the compound of the formula I isadministered in combination with PDE (phosphodiesterase) inhibitors, asdescribed, for example, in WO2003/077949 or WO2005012485.

In one embodiment of the invention, the compound of the formula I isadministered in combination with NAR-1 (nicotinic acid receptor)agonists as described, for example, in WO2004094429.

In one embodiment of the invention, the compound of the formula I isadministered in combination with CB2 (cannabinoid receptor) agonists asdescribed, for example, in US2005/143448.

In one embodiment of the invention, the compound of the formula I isadministered in combination with histamine 1 agonists as described, forexample, in WO2005101979.

In one embodiment of the invention, the compound of the formula I isadministered in combination with bupropion, as described inWO2006017504.

In one embodiment of the invention, the compound of the formula I isadministered in combination with opioid antagonists as described, forexample, in WO2005107806 or WO2004094429.

In one embodiment of the invention, the compound of the formula I isadministered in combination with neutral endopeptidase inhibitors asdescribed, for example, in WO200202513, WO2002/06492, WO 2002040008,WO2002040022 or WO2002047670.

In one embodiment of the invention, the compound of the formula I isadministered in combination with NPY inhibitors (neuropeptide Y) asdescribed, for example, in WO2002047670.

In one embodiment of the invention, the compound of the formula I isadministered in combination with sodium/hydrogen exchange inhibitors asdescribed, for example, in WO2003092694.

In one embodiment of the invention, the compound of the formula I isadministered in combination with modulators of the glucocorticoidreceptor as described, for example, in WO2005090336.

In one embodiment of the invention, the compound of the formula I isadministered in combination with nicotine receptor agonists asdescribed, for example, in WO2004094429.

In one embodiment of the invention, the compound of the formula I isadministered in combination with NRIs (norepinephrine reuptakeinhibitors) as described, for example, in WO2002053140.

In one embodiment of the invention, the compound of the formula I isadministered in combination with MOA (E-beta-methoxyacrylate), such as,for example, segeline, or as described, for example, in WO2002053140.

In one embodiment of the invention, the compound of the formula I isadministered in combination with antithrombotic active ingredients, suchas, for example, clopidogrel.

It is to be understood that each suitable combination of the compoundsaccording to the invention with one or more of the compounds mentionedabove and optionally one or more further pharmacologically activesubstances is meant to be included in the scope of the presentinvention.

The formulae for some of the development codes mentioned above are givenbelow:

The activity of the compounds was tested as follows:

Determination of EC50 Values of PPAR Agonists in the Cellular PPARalphaAssay

Principle

The potency of substances which bind to human PPARalpha and activate itin an agonistic manner is analyzed using a stably transfected HEK cellline (HEK=human embryo kidney) which is referred to here as PPARalphareporter cell line. It contains two genetic elements, a luciferasereporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARalpha fusion protein(GR-GAL4-humanPPARalpha-LBD) which mediates expression of the luciferasereporter element depending on a PPARalpha ligand. The stably andconstitutively expressed fusion protein GR-GAL4-humanPPARalpha-LBD bindsin the cell nucleus of the PPARalpha reporter cell line via the GAL4protein portion to the GAL4 DNA binding motifs 5′-upstream of theluciferase reporter element which is stably integrated in the genome ofthe cell line. There is only weak expression of the luciferase reportergene in the absence of a PPARalpha ligand if fatty acid-depleted fetalcalf serum (cs-FCS) is used in the assay. PPARalpha ligands bind andactivate the PPARalpha fusion protein and thereby stimulate theexpression of the luciferase reporter gene. The luciferase which isformed can be detected by means of chemiluminescence via an appropriatesubstrate.

Construction of the PPARalpha Reporter Cell Line

The PPARalpha reporter cell line was prepared in two stages. Firstly,the luciferase reporter element was constructed and stably transfectedinto HEK cells. For this purpose, five binding sites of the yeasttranscription factor GAL4 (Accession # AF264724) were cloned in5′-upstream of a 68 bp-long minimal MMTV promoter (Accession # V01175).The minimal MMTV promoter section contains a CCAAT box and a TATAelement in order to enable efficient transcription by RNA polymerase II.The cloning and sequencing of the GAL4-MMTV construct took place inanalogy to the description of Sambrook J. et. al. (Molecular cloning,Cold Spring Harbor Laboratory Press, 1989). Then the complete Photinuspyralis gene (Accession # M15077) was cloned in 3′-downstream of theGAL4-MMTV element. After sequencing, the luciferase reporter elementconsisting of five GAL4 binding sites, MMTV promoter and luciferase genewas recloned into a plasmid which confers zeocin resistance in order toobtain the plasmid pdeltaM-GAL4-Luc-Zeo. This vector was transfectedinto HEK cells in accordance with the statements in Ausubel, F. M. etal. (Current protocols in molecular biology, Vol. 1-3, John Wiley &Sons, Inc., 1995). Then zeocin-containing medium (0.5 mg/ml) was used toselect a suitable stable cell clone which showed very low basalexpression of the luceriferase gene.

In a second step, the PPARalpha fusion protein(GR-GAL4-humanPPARalpha-LBD was introduced into the stable cell clonedescribed. For this purpose, initially the cDNA coding for theN-terminal 76 amino acids of the glucocorticoid receptor (Accession #P04150) was linked to the cDNA section coding for amino acids 1-147 ofthe yeast transcription factor GAL4 (Accession # P04386). The cDNA ofthe ligand-binding domain of the human PPARalpha receptor (amino acidsS167-Y468; Accession # S74349) was cloned in at the 3′-end of thisGR-GAL4 construct. The fusion construct prepared in this way(GR-GAL4-humanPPARalpha-LBD) was recloned into the plasmid pcDNA3(Invitrogen) in order to enable constitutive expression therein by thecytomegalovirus promoter. This plasmid was linearized with a restrictionendonuclease and stably transfected into the previously described cellclone containing the luciferase reporter element. The finished PPARalphareporter cell line which contains a luciferase reporter element andconstitutively expresses the PPARalpha fusion protein (GR-GAL4-humanPPARalpha-LBD) was isolated by selection with zeocin (0.5 mg/ml) andG418 (0.5 mg/ml).

Assay Procedure

The activity of PPARalpha agonists is determined in a 3-day assay whichis described below:

Day 1

The PPARalphareporter cell line is cultivated to 80% confluence in DMEM(# 41965-039, Invitrogen) which is mixed with the following additions:10% cs-FCS (fetal calf serum; #SH-30068.03, Hyclone), 0.5 mg/ml zeocin(#R250-01, Invitrogen), 0.5 mg/ml G418 (#10131-027, Invitrogen),1%penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mML-glutamine (#25030-024, Invitrogen). The cultivation takes place instandard cell culture bottles (# 353112, Becton Dickinson) in a cellculture incubator at 37° C. in the presence of 5% CO2. The 80%-confluentcells are washed once with 15 ml of PBS (#14190-094, Invitrogen),treated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37° C.for 2 min, taken up in 5 ml of the DMEM described and counted in a cellcounter. After dilution to 500.000 cells/ml, 35,000 cells are seeded ineach well of a 96 well microtiter plate with a clear plastic base(#3610, Corning Costar). The plates are incubated in the cell cultureincubator at 37° C. and 5% CO2 for 24 h.

Day 2

PPARalpha agonists to be tested are dissolved in DMSO in a concentrationof 10 mM. This stock solution is diluted in DMEM (#41965-039,Invitrogen) which is mixed with 5% cs-FCS (#SH-30068.03, Hyclone), 2 mML-glutamine (#25030-024, Invitrogen) and the previously describedantibiotics (zeocin, G418, penicillin and streptomycin). Test substancesare tested in 11 different concentrations in the range from 10 μM to 100pM. More potent compounds are tested in concentration ranges from 1 μMto 10 pM or between 100 nM and 1 pM.

The medium of the PPARalpha reporter cell line seeded on day 1 iscompletely removed by aspiration, and the test substances diluted inmedium are immediately added to the cells. The dilution and addition ofthe substances is carried out by a robot (Beckman FX). The final volumeof the test substances diluted in medium is 100 μl per well of a 96 wellmicrotiter plate. The DMSO concentration in the assay is less than 0.1%v/v in order to avoid cytotoxic effects of the solvent.

Each plate was charged with a standard PPARalpha agonist, which waslikewise diluted in 11 different concentrations, in order to demonstratethe functioning of the assay in each individual plate. The assay platesare incubated in an incubator at 37° C. and 5% CO2 for 24 h.

Day 3

The PPARalpha reporter cells treated with the test substances areremoved from the incubator, and the medium is aspirated off. The cellsare lyzed by pipetting 50 μl of Bright Glo reagent (from Promega) intoeach well of a 96 well microtiter plate. After incubation at roomtemperature in the dark for 10 minutes, the microtiter plates aremeasured in the luminometer (Trilux from Wallac). The measuring time foreach well of a microtiter plate is 1 sec.

Evaluation

The raw data from the luminometer are transferred into a Microsoft Excelfile. Dose-effect plots and EC50 values of PPAR agonists are calculatedusing the XL.Fit program as specified by the manufacturer (IDBS).

Determination of EC50 Values of PPAR Agonists in the Cellular PPARdeltaAssay

Principle

The potency of substances which bind to human PPARdelta and activate itin an agonistic manner is analyzed using a stably transfected HEK cellline (HEK=human embryo kidney) which is referred to here as PPARdeltareporter cell line. In analogy to the assay described for PPARalpha, thePPARdelta reporter cell line also contains two genetic elements, aluciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARdeltafusion protein (GR-GAL4-humanPPARdelta-LBD) which mediates expression ofthe luciferase reporter element depending on a PPARdelta ligand. Thestably and constitutively expressed fusion proteinGR-GAL4-humanPPARdelta-LBD binds in the cell nucleus of the PPARdeltareporter cell line via the GAL4 protein portion to the GAL4 DNA bindingmotifs 5′-upstream of the luciferase reporter element which is stablyintegrated in the genome of the cell line. There is only littleexpression of the luciferase reporter gene in the absence of a PPARdeltaligand if fatty acid-depleted fetal calf serum (cs-FCS) is used in theassay. PPARdelta ligands bind and activate the PPARdelta fusion proteinand thereby stimulate expression of the luciferase reporter gene. Theluciferase which is formed can be detected by means of chemiluminescencevia an appropriate substrate.

Construction of the PPARdelta Reporter Cell Line

The production of the stable PPARdelta reporter cell line is based on astable HEK-cell clone which was stably transfected with a luciferasereporter element. This step was already described above in the section“construction of the PPARalpha reporter cell line”. In a second step,the PPARdelta fusion protein (GR-GAL4-humanPPARdelta-LBD was stablyintroduced into this cell clone. For this purpose, the cDNA coding forthe N-terminal 76 amino acids of the glucocorticoid receptor (Accession# P04150) was linked to the cDNA section coding for amino acids 1-147 ofthe yeast transcription factor GAL4 (Accession # P04386). The cDNA ofthe ligand-binding domain of the human PPARdelta receptor (amino acidsS139-Y441; Accession # L07592) was cloned in at the 3′-end of thisGR-GAL4 construct. The fusion construct prepared in this way(GR-GAL4-humanPPARdelta-LBD) was recloned into the plasmid pcDNA3(Invitrogen) in order to enable constitutive expression by thecytomegalovirus promoter. This plasmid was linearized with a restrictionendonuclease and stably transfected into the previously described cellclone containing the luciferase reporter element. The resultingPPARdelta reporter cell line which contains a luciferase reporterelement and constitutively expresses the PPARdelta fusion protein(GR-GAL4-human PPARdelta-LBD) was isolated by selection with zeocin (0.5mg/ml) and G418 (0.5 mg/ml).

Assay Procedure and Evaluation

The activity of PPARdelta agonists is determined in a 3-day assay inexact analogy to the procedure already described for the PPARalphareporter cell line except that the PPARdelta reporter cell line and aspecific PPARdelta agonist was used as a standard to control testefficacy.

PPARdelta EC50 values in the range from 1 nM to >10 μM were measured forthe PPAR agonists of Examples 1 to 25 described in this application.Compounds of the invention of the formula I activate the PPARdeltareceptor partially.

Determination of EC50 Values of PPAR Agonists in the Cellular PPARgammaAssay

Principle

A transient transfection system is employed to determine the cellularPPARgamma activity of PPAR agonists. It is based on the use of aluciferase reporter plasmid (pGL3basic-5×GAL4-TK) and of a PPARgammaexpression plasmid (pcDNA3-GAL4-humanPPARgammaLBD). Both plasmids aretransiently transfected into human embryonic kidney cells (HEK cells).There is then expression in these cells of the fusion proteinGAL4-humanPPARgammaLBD which binds to the GAL4 binding sites of thereporter plasmid. In the presence of a PPARgamma-active ligand, theactivated fusion protein GAL4-humanPPARgammaLBD induces expression ofthe luciferase reporter gene, which can be detected in the form of achemiluminescence signal after addition of a luciferase substrate. As adifference from the stably transfected PPARalpha reporter cell line, inthe cellular PPARgamma assay the two components (luciferase reporterplasmid and PPARgamma expression plasmid) are transiently transfectedinto HEK cells because stable and permanent expression of the PPARgammafusion protein is cytotoxic.

Construction of the Plasmids

The luciferase reporter plasmid pGL3basic-5×GAL4-TK is based on thevector pGL3basic from Promega. The reporter plasmid is prepared bycloning five binding sites of the yeast transcription factor GAL4 (eachbinding site with the sequence 5′-CTCGGAGGACAGTACTCCG-3′), together witha 160 bp-long thymidine kinase promoter section (Genbank Accession #AF027128) 5′-upstream into pGL3basic. 3′-downstream of the thymidinekinase promoter is the complete luciferase gene from Photinus pyralis(Genbank Accession # M15077) which is already a constituent of theplasmid pGL3basic used. The cloning and sequencing of the reporterplasmid pGL3basic-5×GAL4-TK took place in analogy to the description inSambrook J. et. al. (Molecular cloning, Cold Spring Harbor LaboratoryPress, 1989). The PPARgamma expression plasmidpcDNA3-GAL4-humanPPARgammaLBD was prepared by first cloning the cDNAcoding for amino acids 1-147 of the yeast transcription factor GAL4(Genbank Accession # P04386) into the plasmid pcDNA3 (from Invitrogen)3′-downstream of the cytomegalovirus promoter. Subsequently, the cDNA ofthe ligand-binding domain (LBD) of the human PPARgamma receptor (aminoacids I152-Y475; Accession # g1480099) 3′-downstream of the GAL4 DNAbinding domain. Cloning and sequencing of the PPARgamma expressionplasmid pcDNA3-GAL4-humanPPARgammaLBD again took place in analogy to thedescription in Sambrook J. et. al. (Molecular cloning, Cold SpringHarbor Laboratory Press, 1989). Besides the luciferase reporter plasmidpGL3basic-5×GAL4-TK and the PPARgamma expression plasmidpcDNA3-GAL4-humanPPARgammaLBD, also used for the cellular PPARgammaassay are the reference plasmid PRL-CMV (from Promega) and the plasmidpBluescript SK(+) from Stratagene. All four plasmids were prepared usinga plasmid preparation kit from Qiagen, which ensured a plasmid qualitywith a minimal endotoxin content, before transfection into HEK cells.

Assay Procedure

The activity of PPARgamma agonists is determined in a 4-day assay whichis described below. Before the transfection, HEK cells are cultivated inDMEM (# 41965-039, Invitrogen) which is mixed with the followingadditions: 10% FCS (#16000-044, Invitrogen), 1% penicillin-streptomycinsolution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024,Invitrogen).

Day 1

Firstly, solution A, a transfection mixture which contains all fourplasmids previously described in addition to DMEM, is prepared. Thefollowing amounts are used to make up 3 ml of solution A for each 96well microtiter plate for an assay: 2622 μl of antibiotic- andserum-free DMEM (# 41965-039, Invitrogen), 100 μl of reference plasmidpRL-CMV (1 ng/μl), 100 μl of luciferase reporter plasmidpGL3basic-5×GAL4-TK (10 ng/μl), 100 μl of PPARgamma expression plasmidpcDNA3-GAL4-humanPPARgammaLBD (100 ng/μl) and 78 μl of plasmidpBluescript SK(+) (500 ng/μl). Then 2 ml of solution B are prepared bymixing 1.9 ml of DMEM (# 41965-039, Invitrogen) with 100 μl of PolyFecttransfection reagent (from Qiagen) for each 96 well microtiter plate.Subsequently, 3 ml of solution A are mixed with 2 ml of solution B togive 5 ml of solution C, which is thoroughly mixed by multiple pipettingand incubated at room temperature for 10 min.

80%-confluent HEK cells from a cell culture bottle with a capacity of175 cm2 are washed once with 15 ml of PBS (#14190-094, Invitrogen) andtreated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37° C.for 2 min. The cells are then taken up in 15 ml of DMEM (# 41965-039,Invitrogen) which is mixed with 10% FCS (# 16000-044, Invitrogen), 1%penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mML-glutamine (#25030-024, Invitrogen). After the cell suspension has beencounted in a cell counter, the suspension is diluted to 250,000cells/ml. 15 ml of this cell suspension are mixed with 5 ml of solutionC for one microtiter plate. 200 μl of the suspension are seeded in eachwell of a 96 well microtiter plate with a clear plastic base (#3610,Corning Costar). The plates are incubated in a cell culture incubator at37° C. and 5% CO2 for 24 h.

Day 2

PPAR agonists to be tested are dissolved in DMSO in a concentration of10 mM. This stock solution is diluted in DMEM (# 41965-039, Invitrogen)which is mixed with 2% Ultroser (#12039-012, Biosepra), 1%penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mML-glutamine (#25030-024, Invitrogen). Test substances are tested in atotal of 11 different concentrations in the range from 10 μM to 100 μM.More potent compounds are tested in concentration ranges from 1 μM to 10μM.

The medium of the HEK cells transfected and seeded on day 1 iscompletely removed by aspiration, and the test substances diluted inmedium are immediately added to the cells. The dilution and addition ofthe substances is carried out by a robot (Beckman FX). The final volumeof the test substances diluted in medium is 100 μl per well of a 96 wellmicrotiter plate. Each plate is charged with a standard PPARgammaagonist, which is likewise diluted in 11 different concentrations, inorder to demonstrate the functioning of the assay in each individualplate. The assay plates are incubated in an incubator at 37° C. and 5%CO2.

Day 4

After removal of the medium by aspiration, 50 μl of Dual-Glo™ reagent(Dual-Glo™ Luciferase Assay System; Promega) are added to each well inaccordance with the manufacturer's instructions in order to lyze thecells and provide the substrate for the firefly luciferase (Photinuspyralis) formed in the cells. After incubation at room temperature inthe dark for 10 minutes, the firefly luciferase-mediatedchemiluminescence is measured in a measuring instrument (measuringtime/well 1 sec; Trilux from Wallac). Then 50 μl of the Dual-Glo™ Stop &Glo reagent (Dual-Glo™ Luciferase Assay System; Promega) is added toeach well in order to stop the activity of the firefly luciferase andprovide the substrate for the Renilla luciferase expressed by thereference plasmid PRL-CMV. After incubation at room temperature in thedark for a further 10 minutes, a chemiluminescence mediated by theRenilla luciferase is again measured for 1 sec/well in the measuringinstrument.

Evaluation

The crude data from the luminometer are transferred into a MicrosoftExcel file. The firefly/Renilla luciferase activity ratio is determinedfor each measurement derived from one well of the microtiter plate. Thedose-effect plots and EC50 values of PPAR agonists are calculated fromthe ratios by the XL.Fit program as specified by the manufacturer(IDBS).

PPARgamma EC50 values in the range from 1 nM to >10 μM were measured forthe PPAR agonists of Examples 1 to 25 described in this application.Compounds of the invention of the formula I activate the PPARgammareceptor partially.

The examples given in Table 1, where a dotted line means the point ofattachment to the amide, serve to illustrate the invention, but withoutlimiting it.

TABLE I

Ex R1 R2 R3 R4 R5 R6 R7 R8 n z A 1 —CH(CH₃)₂ H H H H 2-OCH₂CH₃ 4-CF₃ H 11

1.1 —CH(CH₃)₂ H H H H 2-OCH₂CH₃ 4-CF₃ H Enan. 1 1

1.2 —CH(CH₃)₂ H H H H 2-OCH₂CH₃ 4-CF₃ H Enan. 2 1

2 —CF₃ H H H H 2-OCH₂CH₃ 4-CF₃ H 1 1

3 —CH(CH₃)₂ H H H H 2-(4-CF₃—Ph) 4-CH₃ H 1 1

4 Cyclopropyl H H H H 2-(4-CF₃—Ph) 4-CH₃ H 1 1

5 —CH(CH₃)₂ H H H H 2-OCH₂CH₃ 4-CF₃ H 2 (S) 1

6 —CH(CH₃)₂ H H H H 2-OCH₂CH₃ 4-CF₃ H 2 (R) 1

7 —CH(CH₃)₂ 5-Cl H H H 2-OCH₂CH₃ 4-CF₃ H 1 1

8 —CH(CH₃)₂ 6-OCH₃ H H H 2-OCH₂CH₃ 4-CF₃ H 1 1

9 —CH(CH₃)₂ 5-Cl H H H 3-OCH₂CH₃ 5-CF₃ H 1 1

10 —CH(CH₃)₂ 6-OCH₃ H H H 3-OCH₂CH₃ 5-CF₃ H 1 1

11 —CH(CH₃)₂ H H H H 3-OCH₂CH₃ 5-CF₃ H 1 1

12 —CH(CH₃)₂ H H H H 2-OCH₂CH₃ 4-CF₃ H 2 2

13 —CH(CH₃)₂ H H H H 2-Cl 5-CF₃ H 1 1

14 —CH(CH₃)₂ H H H H 2-CH₃ 4-Cl H 1 1

15 —CH(CH₃)₂ H H H H 2-F 4-CF₃ 3-F 1 1

16 —CH(CH₃)₂ H H H H 2-F 4-CF₃ H 1 1

17 —CH(CH₃)₂ H H H H 2-OCH₃ 4-Cl H 1 1

18 —CH(CH₃)₂ H H H H 2-Cl 4-Cl H 1 1

19 —CH(CH₃)₂ 5-F H H H 2-OCH₂CH₃ 4-CF₃ H 1 1

20 —CH(CH₃)₂ H H H 1-CH₃ 2-OCH₂CH₃ 4-CF₃ H 1 1

21 —CH(CH₃)₂ 6-O—CH₂CF₃ H H H 2-OCH₂CH₃ 4-CF₃ H 1 1

22 Cyclopropyl H H H H 2-OCH₂CH₃ 4-CF₃ H 1 1

23 Phenyl H H H H 2-OCH₂CH₃ 4-CF₃ H 1 1

24 Cyclohexyl H H H H 2-OCH₂CH₃ 4-CF₃ H 1 1

25 —CH(CH₃)₂ H H H H 3-OCH₃ H H 1 1

The potency of some of the described examples are indicated in thefollowing table:

PPARdelta PPARgamma Example EC50 (μM) EC50 (μM) 1 0.001 0.001 1.1 0.0010.022 1.2 0.05 >10 5 0.6 0.1 6 0.6 0.2 11 0.001 >10Processes

The compounds of the general formula I according to the invention whereA, n, z, R1, R2, R3, R4, R5, R6, R7, R8 are as defined can be obtainedas outlined in the reaction schemes below:

An amino bicyclic compound of general formula 2 is treated with anacylating agent like acetic anhydride or acetylchloride to yield theintermediate 3, which on action with chlorosulfonic acid leads thebenzenesulfonyl chloride of general formula 4. The benzenesulfonylchloride of general formula 4 is coupled with the[1,3,4]thiadiazol-2-ylamine of the general formula 5 in the presence ofa base or in a basic solvent like pyridine to obtain the sulfonyl amidethat after refluxing in 2N hydrochloric acid to remove the N-acetylgroup gives the amine of general formula 6 as its hydrochloric acidsalt.

The amine of general formula 6 is coupled with a carboxylic acid ofgeneral formula 7, where X═OH, with a coupling reagent asO-((Ethoxycarbonyl)cyanomethyleneamino)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate in the presence of a base such as triethylamine in anappropriate solvent like dimethylformamide or tetrahydrofuran to obtainthe compound of general formula 1. Alternatively the amine of generalformula 6 is coupled with a carbonyl chloride of general formula 7,where X═Cl—or with other known derivatives of acids that are able toreact with amines—in a solvent as dichloromethane and in the presence ofa base like triethylamine to obtain the compound of general formula 1.

A further method to prepare the compounds of the general formula 1consists in the acylation of the amino indanes 2 with the carboxylicacid derivatives 7 and the subsequent reaction with chloro sulfonic acidfollowed by reaction with the amino heterocycle 5.

LIST OF ABBREVIATION

Ac acetyl AIBN 2,2′-azobis(2-methylpropionitrile) Bn benzyl BOCtert-butyl-oxy-carbonyl iBu isobutyl tBu tert-butyl BuLi n-butyllithiumBz benzoyl Cy cyclohexyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCIdirect chemical ionization (MS) DCM dichloromethane DMAPN,N-dimethylaminopyridine DMF N,N-dimethylformamide DMSOdimethylsulfoxide EE ethyl acetate eq equivalents ESIelectronspray-Ionisation (MS) FG leaving group GC gas chromatography Halhalogen HPLC high performance liquid chromatography LC-MS liquidchromatography coupled with mass-spectroscopy Me methyl MeCNacetonitrile MS mass-spectroscopy MS 4A molecular sieves four angströmMsCl methansulfonylchloride MW micro wave NBS N-bromosuccinimide NMRnuclear magnetic resonance p para Pd/C palladium on carbon iPr isopropylnPr n-propyl Rf retention factor (TLC) tert tertiary TFA trifluoroaceticacid THF tetrahydrofuran TLC thin layer chromatography TOTUO-((ethoxycarbonyl)cyanomethyleneamino)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate

EXPERIMENTAL PART 1)2-Ethoxy-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide

1a) 2-Methoxy-4-trifluoromethoxy-benzoic acid methyl ester

1.0 g 2-hydroxy-(trifluoromethoxy)benzoic acid were dissolved in 30 mldimethylformamide. 640 mg iodomethane and 4.70 g cesium carbonate wereadded and the reaction mixture was stirred at room temperature for threehours. The reaction mixture was diluted by addition of 100 ml ethylacetate, washed with 30 ml water and brine and then dried over MgSO4.The solvent was removed in vacuo to obtain 590 mg2-methoxy-4-trifluoromethoxy-benzoic acid methyl ester.

MS(ESI): (M+1)=251

1b) 2-Methoxy-4-trifluoromethoxy-benzoic acid

590 mg 2-Methoxy-4-trifluoromethoxy-benzoic acid methyl ester wasdissolved in a mixture of 30 ml tetrahydrofuran and 10 ml water. 367 mglithium hydroxide were added and the reaction mixture stirred at 60° C.for two hours. The cooled reaction mixture was acidified by dropwiseaddition of concentrated hydrochloric acid, then the mixture wasextracted three times with portions of 80 ml ethyl acetate. The combinedorganic layers were dried over MgSO4. The solvent was removed in vacuoto obtain 518 mg 2-methoxy-4-trifluoromethoxy-benzoic acid.

MS(ESI): (M+1)=237

1c) N-Indan-2-yl-acetamide

Acetic anhydride (3.55 ml) was dropped to the mixture of 6.37 g 2-aminoindane hydrochloride, 60 ml of ethyl acetate and 10.4 ml triethylamineand the reaction mixture was stirred at room temperature for 15 hours.The solvents were evaporated in vacuo and the solid residue was digestedwith water, filtered and dried at 40° C. in vacuo.

Yield: 5.5 g Mp.: 126.5° C.

1d) 2-Acetylamino-indan-5-sulfonyl chloride

1.6 ml of chloro sulfonic acid was dropped to the stirred solution of1.06 g N-Indan-2-yl-acetamide and 50 ml of dichloromethane and themixture was stirred for 15 hours at room temperature. The reaction wasthan quenched with cold water and die organic phase separated, driedover sodium sulfate evaporated. The resulting residue was used forfurther reaction without further purification.

Yield: 1.4 g

1e)N-[5-(5-Isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-acetamide

2-Acetylamino-indan-5-sulfonyl chloride (500 mg) was dissolved in 5 mlof pyridine and a catalytic amount of 4-dimethylamino pyridine wasadded. After addition of 262 mg of 5-isopropyl-[1,3,4]thiadiazol-2-yla

mine the mixture was stirred at 60° C. for 1 hour followed byevaporation. The resulting crude material was purified by columnchromatography (silica gel, eluent: dichloromethane:methanol=95:5).

Yield: 250 mg MS(ESI): (M+1)=381

1f) N-(5-Sulfamoyl-indan-2-yl)-acetamide

was prepared from 2-Acetylamino-indan-5-sulfonyl chloride and an excessof ammonia.

MS(ESI): (M+1)=255

1g) 2-Amino-indan-5-sulfonic acid(5-isopropyl-[1,3,4]thiadiazol-2-yl)-amide hydrochloride

N-[5-(5-Isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-acetamide(96 mg) was heated and stirred for 27 hours in 10 ml 2N hydrochloricacid at 100° C. After completion a clear solution occurred. This wasevaporated to dryness and the solid residue was used without furtherpurification.

MS(ESI): (M+1)=339

1)2-Ethoxy-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide(A003541307)

The mixture of 2-amino-indan-5-sulfonic acid(5-isopropyl-[1,3,4]thiadiazol-2-yl)-amide hydrochloride (40 mg), 1.5 mlof dimethyl formamide, 0.037 ml of triethylamine, 41 mg of HATU and 25mg of 2-ethoxi-4-trifluoromethyl-benzoic acid was stirred at roomtemperature over night. The solvents were evaporated in vacuo and theresulting crude material was purified by column chromatography (silicagel, eluent: dichloromethane:methanol=95:5).

MS(ESI): (M+1)=555

1.1)2-Ethoxy-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide(Enantiomer 1)

and

1.2)2-Ethoxy-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide(Enantiomer 2)

were prepared by separation of the racemic compound of example 1 on achiral column (chiralcel OJ-H/73, eluent: MeOH+0.1% TFA, 30° C.)

2)2-Ethoxy-4-trifluoromethyl-N-[5-(5-trifluoromethyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-benzamide

was prepared by a method similar to example 1) starting with theintermediate of example 2a).

MS(ESI): (M+1)=581

2a)N-[5-(5-Trifluoromethyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-acetamide

The mixture of 300 mg of 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazol,300 mg of N-(5-sulfamoyl-indan-2-yl)-acetamide, 1.8 g cesium carbonateund 10 ml of NMP was stirred at 70° C. for 3 hours. After cooling toroom temperature 50 ml of water were added and with 2N hydrochloric acida pH=3 was adjusted. The product was extracted twice with 30 ml of ethylacetate, the organic layer was washed with 20 ml of water, dried oversodium sulfate and evaporated in vacuo. The resulting crude material waspurified by column chromatography (silica gel, eluent:dichloromethane:methanol=90:10).

MS(ESI): (M+1)=407

The following compounds were prepared by similar methods: 3)4-Methyl-2-(4-trifluormethyl-phenyl)-thiazol-5-carbonsäure-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-amid

MS(ESI): (M+1)=608

4)4-Methyl-2-(4-trifluormethyl-phenyl)-thiazol-5-carbonsäure-[5-(5-cyclopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-amid

MS(ESI): (M+1)=606

5)2-Ethoxy-N—[(S)-7-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-4-trifluoromethyl-benzamide

was prepared by a method similar to example 1) starting with theintermediate of example 5d).

MS(ESI): (M+1)=569

5a) (S)—N-(1,2,3,4-Tetrahydro-naphthalen-2-yl)-acetamide

was prepared by reaction of the commercially available(S)-7-amino-5,6,7,8-tetrahydro-naphthalene with acetic anhydrideaccording to known methods.

MS(ESI): (M+1)=190

5b) (S)-7-Acetylamino-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl chloride

was prepared by sulfochlorination of the compound of the example 5a)with chloro sulfonic acid.

MS(ESI): (M+1)=288

5c)(S)—N—[(S)-7-(5-Isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-1,2,3,4-tetrahydro-naphthalene-2-yl]-acetamide

was prepared by reaction of the compound of the example 5b) with5-isopropyl-(1,3,4)-thiadiazol-ylamine in pyridine.

MS(ESI): (M+1)=395

5d) (S)-7-Amino-5,6,7,8-tetrahydro-naphthalene-2-sulfonicacid-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-amide-hydrochloride

was prepared by reaction of the compound of the example 5c) with 5Nhydrochloric acid at 100° C. for 25 hours.

MS(ESI): (M+1)=353

6)2-Ethoxi-N—[(R)-7-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-1,2,3,4-tetrahydro-naphthalene-2-yl]-4-trifluoromethyl-benzamide

was prepared by a reaction sequence similar to the preparation of thecompound of example 5) starting with the commercially available(R)-7-amino-5,6,7,8-tetrahydro-naphthalene.

MS(ESI): (M+1)=569

7)N-[5-Chloro-6-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-2-ethoxy-4-trifluoromethyl-benzamide

was prepared by a reaction sequence similar to the preparation of thecompound of example 1) starting with 5-chloro-indan-2-ylamine.

MS(ESI): (M+1)=589

8)2-Ethoxy-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-6-methoxy-indan-2-yl]-4-trifluoromethyl-benza

was prepared by a reaction sequence similar to the preparation of thecompound of example 1) starting with 5-methoxy-indan-2-ylamine.

MS(ESI): (M+1)=585

9) 3-Ethoxy-5-trifluoromethyl-thiophene-2-carboxylic acid[5-chloro-6-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-amide

This compound was prepared by reaction of2-Amino-6-chloro-indan-5-sulfonic acid(5-isopropyl-[1,3,4]thiadiazol-2-yl)-hydrochloride with3-ethoxy-5-trifluoromethyl-thiophene-2-carboxylic acid (mp.: 143.7° C.)obtained from 3-ethoxy-5-trifluoromethyl-thiophene-2-carboxylic acidmethyl ester by hydrolysis with lithium hydroxide in water/methanol.

The 3-ethoxy-5-trifluoromethyl-thiophene-2-carboxylic acid methyl ester(mp.: 93.6° C.) was prepared from the known3-hydroxy-5-trifluoromethyl-thiophene-2-carboxylic acid methyl ester(Synthesis 2000, No. 8, 1078-1080) by alkylation with ethyliodide in thepresence of cesium carbonate in DMF as solvent.

MS(ESI):MS(ESI): (M+1)=595

10) 3-Ethoxy-5-trifluoromethyl-thiophene-2-carboxylic acid[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-6-methoxy-indan-2-yl]-amide

This compound was prepared similarly by reaction of2-Amino-6-methoxi-indan-5-sulfonic acid(5-isopropyl-[1,3,4]thiadiazol-2-yl)-hydrochloride with3-ethoxy-5-trifluoromethyl-thiophene-2-carboxylic acid.

MS(ESI): (M+1)=591

11) 3-Ethoxy-5-trifluoromethyl-thiophene-2-carboxylic acid[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-amide

This compound was prepared similarly by reaction of2-Amino-indan-5-sulfonic acid(5-isopropyl-[1,3,4]thiadiazol-2-yl)-hydrochloride with3-ethoxy-5-trifluoromethyl-thiophene-2-carboxylic acid.

MS(ESI): (M+1)=561

12)2-Ethoxy-N-[2-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl]-4-trifluoromethyl-benzamide

was prepared by a reaction sequence similar to the preparation of thecompound of example 1) starting with6,7,8,9-tetrahydro-5H-enzocyclohepten-7-ylamine.

MS(ESI): (M+1)=583

13)2-Chloro-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-5-trifluoromethyl-benzamide

This compound was prepared similarly by reaction of2-amino-indan-5-sulfonic acid(5-isopropyl-[1,3,4]thiadiazol-2-yl)-hydrochloride with2-chloro-5-trifluoromethyl-benzoic acid.

MS(ESI): (M+1)=545

14)4-Chloro-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-2-methyl-benzamide

This compound was prepared similarly by reaction of2-amino-indan-5-sulfonic acid(5-isopropyl-[1,3,4]thiadiazol-2-yl)-hydrochloride with4-chloro-2-methyl-benzoic acid.

MS(ESI): (M+1)=491

15)2,3-Difluoro-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide

This compound was prepared similarly by reaction of2-amino-indan-5-sulfonic acid(5-isopropyl-[1,3,4]thiadiazol-2-yl)-hydrochloride with 2,3-difluoro4-trifluoromethyl-benzoic acid.

MS(ESI): (M+1)=547

16)2-Fluoro-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide

This compound was prepared similarly by reaction of2-amino-indan-5-sulfonic acid(5-isopropyl-[1,3,4]thiadiazol-2-yl)-hydrochloride with 2-fluoro4-trifluoromethyl-benzoic acid.

MS(ESI): (M+1)=529

17)4-Chloro-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-2-methoxi-benzamide

This compound was prepared similarly by reaction of2-amino-indan-5-sulfonic acid(5-isopropyl-[1,3,4]thiadiazol-2-yl)-hydrochloride with4-chloro-2-methoxy-benzoic acid.

MS(ESI): (M+1)=507

18)2,4-Dichloro-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-benzamide

This compound was prepared similarly by reaction of2-amino-indan-5-sulfonic acid(5-isopropyl-[1,3,4]thiadiazol-2-yl)-hydrochloride with2,4-dichloro-benzoic acid.

MS(ESI): (M+1)=511

19)2-Ethoxy-N-[5-fluoro-6-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide

This compound was prepared similarly to the procedure described inexample 1 starting from 5-fluoro-indan-2-yl-amine.

MS(ESI): (M+1)=573

20)2-Ethoxy-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-1-methyl-indan-2-yl]-4-trifluoromethyl-benzamide

This compound was prepared similarly to the procedure described inexample 1 starting from 1-methyl-indan-2-yl-amine.

MS(ESI): (M+1)=569

21)2-Ethoxy-N-[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-6-(2,2,2-trifluoro-ethoxy)-indan-2-yl]-4-trifluoromethyl-benzamide

This compound was prepared similarly to the procedure described inexample 1 starting from 5-(2,2,2-trifluoro-ethoxy)-indan-2-yl-amine.

MS(ESI): (M+1)=653

22)N-[5-(5-Cyclopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-2-ethoxy-4-trifluoromethyl-benzamide

This compound was prepared similarly to the procedure described inexample 1 starting from 5-cyclopropyl-[1,3,4]thiadiazol-2-ylamine.

MS(ESI): (M+1)=553

23)2-Ethoxy-N-[5-(5-phenyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide

This compound was prepared similarly to the procedure described inexample 1 starting from 5-phenyl-[1,3,4]thiadiazol-2-ylamine.

MS(ESI): (M+1)=589

24)2-Ethoxy-N-[5-(5-cyclhexyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-4-trifluoromethyl-benzamide

This compound was prepared similarly to the procedure described inexample 1 starting from 5-cyclohexyl-[1,3,4]thiadiazol-2-ylamine.

MS(ESI): (M+1)=595

25) 3-Methoxy-pyridine-2-carboxylic acid[5-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-amide

This compound was prepared similarly to the procedure described inexample 1 starting from 3-methoxy-pyridine-2-carboxylic acid.

MS(ESI): (M+1)=474

1. A compound of formula I:

wherein R1 is selected from the group consisting of (C1-C6) alkyl,(C0-C6) alkylene (C3-C6) cycloalkyl, (C0-C6) alkylene-O—(C1-C6) alkyl,(C0-C6) alkylene-O—(C3-C6) cycloalkyl (C0-C6) alkylene-(C6-C14) aryl and(C0-C6) alkylene-(C5-C15) heteroaryl, wherein the alkyl, alkylene, aryl,heteroaryl and cycloalkyl can be unsubstituted or mono-, di- ortri-substituted by F, Cl, Br, OCF₃, CN, CO—(C1-C6) alkyl, COO(C1-C6)alkyl, CON((C0-C6) alkylene-H)((C0-C6) alkylene-H), or S(O)_(m) (C1-C6)alkyl; R2, R3, R4 and R5 are independently selected from the groupconsisting of H, halogen, (C1-C6) alkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-H, CN, COO(C1-C6) alkyl,CON((C0-C6)alkylene-H)((C0-C6)alkylene-H) and S(O)_(m)(C1-C6) alkyl,wherein the alkyl and alkylene are unsubstituted or mono-, di- ortri-substituted by F; A is (C4-C10) heteroaryl; n is 1, 2, or 3; m and zare independently 0, 1, or 2; and R6, R7 and R8 are independentlyselected from the group consisting of H, (C1-C6) alkyl, CN, CO—(C1-C6)alkyl, COO—(C1-C6) alkyl, CON((C0-C6) alkylene-H((C0-C6) alkylene-H),S(O)_(m)(C1-C6) alkyl, N((C0-C6) alkylene-H)((C0-C6) alkylene-H),N((C0-C6) alkylene-H)—CO—(C1-C6) alkyl, N((C0-C6) alkylene-H)—CO—(C1-C6)alkyl, halogen, (C0-C6) alkylene-(C6-C14) aryl (C0-C6)alkylene-O—(C0-C6) alkylene-H, (C0-C6) alkylene-O—(C6-C14) aryl, SCF3,S(O)2CF3 and NO2, wherein the alkyl, aryl and alkylene are unsubstitutedor mono-, di- or tri-substituted by F, and the aryl can also beunsubstituted or monosubstituted by CF3; or a stereoisomer, enantiomer,tautomer, or physiologically acceptable salt thereof.
 2. The compoundaccording to claim 1, wherein R1 is selected from the group consistingof (C1-C6) alkyl, (C0-C6) alkylene-(C3-C6) cycloalkyl, (C0-C6)alkylene-O—(C1-C6) alkyl, (C0-C6) alkylene-O—(C3-C6) cycloalkyl and(C0-C6) alkylene-(C6-C14) aryl, wherein the alkyl, alkylene, aryl, andcycloalkyl can be unsubstituted or mono-, di- or tri-substituted by F,Cl, or Br; R2, R3, R4, R5 are independently selected from the groupconsisting of H, halogen, (C1-C6) alkyl, and (C0-C4) alkylene-O—(C0-C4)alkylene-H, wherein the alkyl and alkylene are unsubstituted or mono-,di- or tri-substituted by F; n is 1, or 2; z is 1, or 2; and R6, R7 andR8 are independently selected from the group consisting of H, (C1-C6)alkyl, CN, halogen, (C0-C6) alkylene-O—(C0-C6) alkylene-H, (C0-C6)alkylene-(C6-C14) aryl, (C0-C6) alkylene-O—(C6-C14) aryl, SCF3, andS(O)2CF3, wherein the alkyl, aryl and alkylene are unsubstituted ormono-, di- or tri-substituted by F, or the aryl can be unsubstituted ormonosubstituted by CF3; or a stereoisomer, enantiomer, tautomer, orphysiologically acceptable salt thereof.
 3. The compound according toclaim 1, wherein R1 is selected from the group consisting of (C1-C6)alkyl, (C0-C6) alkylene (C3-C6) cycloalkyl and (C0-C6) alkylene-(C6-C14)aryl, wherein the alkyl, alkylene, aryl, and cycloalkyl can beunsubstituted or mono, di- or tri substituted by F; R2, R3, R4 and R5are independently selected from the group consisting of H, halogen,(C1-C6) alkyl and (C0-C4) alkylene-O—(C0-C4) alkylene-H, wherein thealkyl and alkylene are unsubstituted or mono-, di- or tri-substituted byF; A is pyridine or thiophene; n is 1; z is 1; R6 is F, Cl, Br, orO(C1-C4)-alkyl, and is in the ortho position; R7 is F, Cl, Br, CH3 orCF3, and is in the para position; and R8 is H; or a stereoisomer,enantiomer, tautomer, or physiologically acceptable salt thereof.
 4. Thecompound according to claim 1, wherein: R1 is selected from the groupconsisting of (C1-C4) alkyl, (C0-C2) alkylene (C3-C6) cycloalkyl and(C0-C2) alkylene-(C6-C10) aryl, wherein the alkyl, aryl, and cycloalkylcan be unsubstituted or mono-, di- or tri-substituted by F; R2 isselected from the group consisting of H, halogen, (C1-C6) alkyl andO—(C0-C4) alkylene-H, wherein the alkyl and alkylene are unsubstitutedor mono-, di- or tri-substituted by F; R3 is H; R4 is H; R5 is H, or(C1-C4) alkyl; A is (C5-C6) heteroaryl; n is 1, or 2; z is 1; R6 isselected from the group consisting of (C1-C4) alkyl, halogen, (C0-C2)alkylene-O—(C0-C6) alkylene-H and (C0-C2) alkylene-(C6-C10) aryl,wherein the alkyl, aryl and alkylene are unsubstituted or mono-, di- ortri-substituted by F, and the aryl also can be unsubstituted ormonosubstituted by CF3; R7 is selected from the group consisting of H,(C1-C4) alkyl and halogen, wherein the alkyl is unsubstituted or mono-,di- or tri-substituted by F; and R8 is H or F; or a stereoisomer,enantiomer, tautomer, or physiologically acceptable salt thereof.
 5. Thecompound according to claim 1, wherein R1 is selected from the groupconsisting of (C1-C4) alkyl, (C3-C6) cycloalkyl, and phenyl, wherein thealkyl can be unsubstituted or mono-, di- or tri-substituted by F; R2 isselected from the group consisting of H, F, Cl and O—(C1-C4) alkylene-H,wherein the alkylene is unsubstituted or mono-, di- or tri-substitutedby F; R3 is H; R4 is H; R5 is H or (C1-C4) alkyl; A is thiophene,thiazole, or pyridine; n is 1, or 2; z is 1; R6 is selected from thegroup consisting of (C1-C4) alkyl, F, C₁₋₁₀—(C0-C6) alkylene-H, andphenyl, wherein the phenyl can be unsubstituted or monosubstituted byCF3; R7 is selected from the group consisting of H, (C1-C4) alkyl, andCl, wherein the alkyl is unsubstituted or mono-, di- or tri-substitutedby F; and R8 is H or F, or a stereoisomer, enantiomer, tautomer, orphysiologically acceptable salt thereof.
 6. The compound according toclaim 1, wherein R1 is isopropyl; R2, R3, R4 and R5 are H; A isthiophene; n is 1; z is 1; R6 is O-ethyl, and is in ortho position; R7is C1 or CF3, and is in the in para position; and R8 is H; or astereoisomer, enantiomer, tautomer, or physiologically acceptable saltthereof.
 7. A pharmaceutical composition comprising at least onecompound according to claim 1, or a stereoisomer, enantiomer, tautomer,or physiologically acceptable salt thereof, in combination with apharmaceutically acceptable carrier or excipient.
 8. The pharmaceuticalcomposition according to claim 7, further comprising at least oneadditional active pharmaceutical compound, wherein the additional activepharmaceutical compound is effective in the treatment of metabolicdisturbance or a physiological disorder associated therewith.
 9. Thepharmaceutical composition according to claim 8 wherein the additionalactive pharmaceutical compound is an anti-diabetic compound effective inthe treatment of diabetes.
 10. The pharmaceutical composition accordingto claim 8 wherein the additional active pharmaceutical compound is alipid modulator compound.
 11. The pharmaceutical composition accordingto claim 8 wherein the additional active pharmaceutical compound is acompound effective in the treatment of metabolic syndrome or a physicalmanifestation thereof.
 12. A pharmaceutical composition comprising atleast one compound according to claim 2, or a stereoisomer, enantiomer,tautomer, or physiologically acceptable salt thereof, in combinationwith a pharmaceutically acceptable carrier or excipient.
 13. Apharmaceutical composition comprising at least one compound according toclaim 3, or a stereoisomer, enantiomer, tautomer, or physiologicallyacceptable salt thereof, in combination with a pharmaceuticallyacceptable carrier or excipient.
 14. A pharmaceutical compositioncomprising at least one compound according to claim 4, or astereoisomer, enantiomer, tautomer, or physiologically acceptable saltthereof, in combination with a pharmaceutically acceptable carrier orexcipient.
 15. A pharmaceutical composition comprising at least onecompound according to claim 5, or a stereoisomer, enantiomer, tautomer,or physiologically acceptable salt thereof, in combination with apharmaceutically acceptable carrier or excipient.
 16. A pharmaceuticalcomposition comprising at least one compound according to claim 6, or astereoisomer, enantiomer, tautomer, or physiologically acceptable saltthereof, in combination with a pharmaceutically acceptable carrier orexcipient.
 17. A method for treating type-2 diabetes or diabetesmellitus or a physical manifestation in a patient in need thereof,comprising administering to the patient a pharmaceutically effectiveamount of the compound according to claim 1, or a stereoisomer,enantiomer, tautomer, or physiologically acceptable salt thereof.
 18. Aprocess for preparing a pharmaceutical composition comprising at leastone compound according to claim 1, or a stereoisomer, enantiomer,tautomer, or physiologically acceptable salt thereof, in combinationwith a pharmaceutically acceptable carrier or excipient, which comprisesmixing the compound according to claim 1 or the stereoisomer,enantiomer, tautomer, or physiologically acceptable salt thereof, withthe pharmaceutically acceptable carrier or excipient, and bringing thismixture into a form suitable for administration.